Certain amino-pyridazines, compositions thereof, and methods of their use

ABSTRACT

Provided are compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X and m are as defined herein. 
     Also provided is a pharmaceutically acceptable composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof. 
     Also provided are methods of using a compound of Formula I, or a pharmaceutically acceptable salt thereof.

This application claims the benefit of U.S. Provisional Application Nos.61/327,538, filed Apr. 23, 2010, and 61/412,302, filed Nov. 10, 2010,each of which is incorporated by reference in its entirety for allpurposes.

The cytoskeleton of skeletal and cardiac muscle cells is unique comparedto that of all other cells. It consists of a nearly crystalline array ofclosely packed cytoskeletal proteins called the sarcomere. The sarcomereis elegantly organized as an interdigitating array of thin and thickfilaments. The thick filaments are composed of myosin, the motor proteinresponsible for transducing the chemical energy of ATP hydrolysis intoforce and directed movement. The thin filaments are composed of actinmonomers arranged in a helical array. There are four regulatory proteinsbound to the actin filaments, which allows the contraction to bemodulated by calcium ions. An influx of intracellular calcium initiatesmuscle contraction; thick and thin filaments slide past each otherdriven by repetitive interactions of the myosin motor domains with thethin actin filaments.

Of the thirteen distinct classes of myosin in human cells, the myosin-IIclass is responsible for contraction of skeletal, cardiac, and smoothmuscle. This class of myosin is significantly different in amino acidcomposition and in overall structure from myosin in the other twelvedistinct classes. Myosin-II forms homo-dimers resulting in two globularhead domains linked together by a long alpha-helical coiled-coiled tailto form the core of the sarcomere's thick filament. The globular headshave a catalytic domain where the actin binding and ATPase functions ofmyosin take place. Once bound to an actin filament, the release ofphosphate (cf. ADP-Pi to ADP) signals a change in structuralconformation of the catalytic domain that in turn alters the orientationof the light-chain binding lever arm domain that extends from theglobular head; this movement is termed the powerstroke. This change inorientation of the myosin head in relationship to actin causes the thickfilament of which it is a part to move with respect to the thin actinfilament to which it is bound. Un-binding of the globular head from theactin filament (Ca²⁺ regulated) coupled with return of the catalyticdomain and light chain to their starting conformation/orientationcompletes the catalytic cycle, responsible for intracellular movementand muscle contraction.

Tropomyosin and troponin mediate the calcium effect on the interactionon actin and myosin. The troponin complex is comprised of threepolypeptide chains: troponin C, which binds calcium ions; troponin I,which binds to actin; and troponin T, which binds to tropomyosin. Theskeletal troponin-tropomyosin complex regulates the myosin binding sitesextending over several actin units at once.

Troponin, a complex of the three polypeptides described above, is anaccessory protein that is closely associated with actin filaments invertebrate muscle. The troponin complex acts in conjunction with themuscle form of tropomyosin to mediate the Ca²⁺ dependency of myosinATPase activity and thereby regulate muscle contraction. The troponinpolypeptides T, I, and C, are named for their tropomyosin binding,inhibitory, and calcium binding activities, respectively. Troponin Tbinds to tropomyosin and is believed to be responsible for positioningthe troponin complex on the muscle thin filament. Troponin I binds toactin, and the complex formed by troponins I and T, and tropomyosininhibits the interaction of actin and myosin. Skeletal troponin C iscapable of binding up to four calcium molecules. Studies suggest thatwhen the level of calcium in the muscle is raised, troponin C exposes abinding site for troponin I, recruiting it away from actin. This causesthe tropomyosin molecule to shift its position as well, thereby exposingthe myosin binding sites on actin and stimulating myosin ATPaseactivity.

Human skeletal muscle is composed of different types of contractilefibers, classified by their myosin type and termed either slow or fastfibers. Table 1 summarizes the different proteins that make up thesetypes of muscle.

TABLE 1 Muscle Fiber Type Fast skeletal Slow Skeletal Myosin Heavy ChainIIa, (IIb*), IIx/d Cardiac β Troponin I (TnI) TnI fast SK TnI slow SKTroponin T (TnT) TnT fast SK TnT slow SK Troponin C (TnC) TnC fast SKTnC slow/cardiac Tropomyosin TM-β/TM-α/TPM 3 TM-β/TM-αs *MHC IIb is notexpressed in human muscle but is present in rodents and other mammals.

In healthy humans most skeletal muscles are composed of both fast andslow fibers, although the proportions of each vary with muscle type.Slow skeletal fibers, often called type I fibers, have more structuralsimilarity with cardiac muscle and tend to be used more for fine andpostural control. They usually have a greater oxidative capacity and aremore resistant to fatigue with continued use. Fast skeletal musclefibers, often called type II fibers, are classified into fast oxidative(IIa) and fast glycolytic (type IIx/d) fibers. While these muscle fibershave different myosin types, they share many components including thetroponin and tropomyosin regulatory proteins. Fast skeletal musclefibers tend to exert greater force but fatigue faster than slow skeletalmuscle fibers and are functionally useful for acute, large scalemovements such as rising from a chair or correcting falls.

Muscle contraction and force generation is controlled through nervousstimulation by innervating motor neurons. Each motor neuron mayinnervate many (approximately 100-380) muscle fibers as a contractilewhole, termed a motor unit. When a muscle is required to contract, motorneurons send stimuli as nerve impulses (action potentials) from thebrain stem or spinal cord to each fiber within the motor unit. Thecontact region between nerve and muscle fibers is a specialized synapsecalled the neuromuscular junction (NMJ). Here, membrane depolarizingaction potentials in the nerve are translated into an impulse in themuscle fiber through release of the neurotransmitter acetylcholine(ACh). ACh triggers a second action potential in the muscle that spreadsrapidly along the fiber and into invaginations in the membrane, termedt-tubules. T-tubules are physically connected to Ca2+ stores within thesarcoplasmic reticulum (SR) of muscle via the dihydropyridine receptor(DHPR). Stimulation of the DHPR activates a second Ca2+ channel in theSR, the ryanodine receptor, to trigger the release of Ca2+ from storesin the SR to the muscle cytoplasm where it can interact with thetroponin complex to initiate muscle contraction. If muscle stimulationstops, calcium is rapidly taken back up into the SR through the ATPdependent Ca2+ pump, SERCA.

Muscle function can become compromised in disease by many mechanisms.Examples include the frailty associated with old age (termed sarcopenia)and cachexia syndromes associated with diseases such as cancer, heartfailure, chronic obstructive pulmonary disease (COPD), and chronickidney disease/dialysis. Severe muscular dysfunction can arise fromneuromuscular diseases (such as Amyotrophic Lateral Sclerosis (ALS),spinal muscular atrophy (SMA) and myasthenia gravis) or muscularmyopathies (such as muscular dystrophies). Additionally, muscle functionmay become compromised due to rehabilitation-related deficits, such asthose associated with recovery from surgery (e.g. post-surgical muscleweakness), prolonged bed rest, or stroke rehabilitation. Additionalexamples of diseases or conditions where muscle function becomescompromised include peripheral vascular disease (e.g., claudication),chronic fatigue syndrome, metabolic syndrome, and obesity.

Accordingly, there is a need for the development of new compounds thatmodulate skeletal muscle contractility. There remains a need for agentsthat exploit new mechanisms of action and which may have better outcomesin terms of relief of symptoms, safety, and patient mortality, bothshort-term and long-term and an improved therapeutic index.

Provided is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, X and m are as defined herein.

Also provided is a pharmaceutically acceptable composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof.

Also provided are methods for treating a disease or condition responsiveto modulation of the contractility of the skeletal sarcomere, forexample, modulation of the troponin complex of the fast skeletal musclesarcomere through one or more of fast skeletal myosin, actin,tropomyosin, troponin C, troponin I, and troponin T, and fragments andisoforms thereof.

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

Throughout this application, unless the context indicates otherwise,references to a compound of Formula I includes all subgroups of FormulaI defined herein, including all substructures, subgenera, preferences,embodiments, examples and particular compounds defined and/or describedherein.

References to a compound of Formula I and subgroups thereof includeionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates,co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides,S-oxides), esters, prodrugs, isotopes and/or protected forms thereof.“Crystalline form,” “polymorph,” and “novel form” may be usedinterchangeably herein, and are meant to include all crystalline andamorphous forms of the compound, including, for example, polymorphs,pseudopolymorphs, solvates (including hydrates), co-crystals, unsolvatedpolymorphs (including anhydrates), conformational polymorphs, andamorphous forms, as well as mixtures thereof, unless a particularcrystalline or amorphous form is referred to. In some embodiments,references to a compound of Formula I and subgroups thereof includepolymorphs, solvates, co-crystals, isomers, tautomers and/or oxidesthereof. In some embodiments, references to a compound of Formula I andsubgroups thereof include polymorphs, salts, solvates, and/orco-crystals thereof. In some embodiments, references to a compound ofFormula I and subgroups thereof include isomers, tautomers and/or oxidesthereof. In some embodiments, references to a compound of Formula I andsubgroups thereof include solvates thereof. Similarly, the term “salts”includes solvates of salts of compounds.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined herein. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible, and/or inherentlyunstable.

When a range of values is given (e.g., C₁₋₆ alkyl), each value withinthe range as well as all intervening ranges are included. For example,“C₁₋₆ alkyl” includes C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₂₋₆, C₃₋₆, C₄₋₆,C₅₋₆, C₁₋₅, C₂₋₅, C₃₋₅, C₄₋₅, C₁₋₄, C₂₋₄, C₃₋₄, C₁₋₃, C₂₋₃, and C₁₋₂alkyl.

When a moiety is defined as being optionally substituted, it may besubstituted as itself or as part of another moiety. For example, ifR^(x) is defined as “C₁₋₆ alkyl or OC₁₋₆ alkyl, wherein C₁₋₆ alkyl isoptionally substituted with halogen”, then both the C₁₋₆ alkyl groupalone and the C₁₋₆ alkyl that makes up part of the OC₁₋₆ alkyl group maybe substituted with halogen.

“Alkyl” encompasses straight and branched carbon chains having theindicated number of carbon atoms, for example, from 1 to 20 carbonatoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, C₁₋₆alkyl encompasses both straight and branched chain alkyl of from 1 to 6carbon atoms. When an alkyl residue having a specific number of carbonsis named, all branched and straight chain versions having that number ofcarbons are intended to be encompassed; thus, for example, “propyl”includes n-propyl and isopropyl; and “butyl” includes n-butyl,sec-butyl, isobutyl and t-butyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl,hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. “Lower alkyl” refers toalkyl groups having 1 to 6 carbons.

“Haloalkyl” includes straight and branched carbon chains having theindicated number of carbon atoms (e.g., 1 to 6 carbon atoms) substitutedwith at least one halogen atom. In instances wherein the haloalkyl groupcontains more than one halogen atom, the halogens may be the same (e.g.,dichloromethyl) or different (e.g., chlorofluoromethyl). Examples ofhaloalkyl groups include, but are not limited to, chloromethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-chloroethyl,2,2-dichloroethyl, 2,2,2-trichloroethyl, 1,2-dichloroethyl,pentachloroethyl, and pentafluoroethyl.

“Alkenyl” refers to an unsaturated branched or straight-chain alkylgroup having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to6 carbon atoms) and at least one carbon-carbon double bond derived bythe removal of one molecule of hydrogen from adjacent carbon atoms ofthe corresponding alkyl. The group may be in either the cis or transconfiguration (Z or E configuration) about the double bond(s). Alkenylgroups include, but are not limited to, ethenyl, propenyl (e.g.,prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl),and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl). “Lower alkenyl” refers toalkenyl groups having 2 to 6 carbons.

“Alkynyl” refers to an unsaturated branched or straight-chain alkylgroup having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to6 carbon atoms) and at least one carbon-carbon triple bond derived bythe removal of two molecules of hydrogen from adjacent carbon atoms ofthe corresponding alkyl. Alkynyl groups include, but are not limited to,ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl) and butynyl(e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl). “Lower alkynyl”refers to alkynyl groups having 2 to 6 carbons.

“Cycloalkyl” indicates a non-aromatic, fully saturated carbocyclic ringhaving the indicated number of carbon atoms, for example, 3 to 10, or 3to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups may be monocyclicor polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl andcyclohexyl, as well as bridged and caged ring groups (e.g., norbornane,bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkylgroup may be aromatic, provided the polycyclic cycloalkyl group is boundto the parent structure via a non-aromatic carbon. For example, a1,2,3,4-tetrahydronaphthalen-1-yl group (wherein the moiety is bound tothe parent structure via a non-aromatic carbon atom) is a cycloalkylgroup, while 1,2,3,4-tetrahydronaphthalen-5-yl (wherein the moiety isbound to the parent structure via an aromatic carbon atom) is notconsidered a cycloalkyl group. Examples of polycyclic cycloalkyl groupsconsisting of a cycloalkyl group fused to an aromatic ring are describedbelow.

“Cycloalkenyl” indicates a non-aromatic carbocyclic ring, containing theindicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6ring carbon atoms) and at least one carbon-carbon double bond derived bythe removal of one molecule of hydrogen from adjacent carbon atoms ofthe corresponding cycloalkyl. Cycloalkenyl groups may be monocyclic orpolycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groupsinclude cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl,and cyclohexenyl, as well as bridged and caged ring groups (e.g.,bicyclo[2.2.2]octene). In addition, one ring of a polycycliccycloalkenyl group may be aromatic, provided the polycyclic alkenylgroup is bound to the parent structure via a non-aromatic carbon atom.For example, inden-1-yl (wherein the moiety is bound to the parentstructure via a non-aromatic carbon atom) is considered a cycloalkenylgroup, while inden-4-yl (wherein the moiety is bound to the parentstructure via an aromatic carbon atom) is not considered a cycloalkenylgroup. Examples of polycyclic cycloalkenyl groups consisting of acycloalkenyl group fused to an aromatic ring are described below.

“Aryl” indicates an aromatic carbon ring having the indicated number ofcarbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms. Aryl groupsmay be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In someinstances, both rings of a polycyclic aryl group are aromatic (e.g.,naphthyl). In other instances, polycyclic aryl groups may include anon-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl) fused to an aromatic ring, provided the polycyclicaryl group is bound to the parent structure via an atom in the aromaticring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (wherein themoiety is bound to the parent structure via an aromatic carbon atom) isconsidered an aryl group, while 1,2,3,4-tetrahydronaphthalen-1-yl(wherein the moiety is bound to the parent structure via a non-aromaticcarbon atom) is not considered an aryl group. Similarly, a1,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound tothe parent structure via an aromatic carbon atom) is considered an arylgroup, while 1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moietyis bound to the parent structure via a non-aromatic nitrogen atom) isnot considered an aryl group. However, the term “aryl” does notencompass or overlap with “heteroaryl”, as defined herein, regardless ofthe point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl areheteroaryl groups). In some instances, aryl is phenyl or naphthyl. Incertain instances, aryl is phenyl. Additional examples of aryl groupscomprising an aromatic carbon ring fused to a non-aromatic ring aredescribed below.

“Aralkyl” refers to a residue having the indicated number of carbonatoms (e.g., 7 to 12 or 7 to 10 carbon atoms) in which an aryl moiety isattached to the parent structure via an alkyl residue. The alkyl residuemay be straight-chain or branched. Examples include, benzyl, phenethyland 1-phenylethyl.

“Heteroaryl” indicates an aromatic ring containing the indicated numberof atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up of oneor more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, Oand S and with the remaining ring atoms being carbon. Heteroaryl groupsdo not contain adjacent S and O atoms. In some embodiments, the totalnumber of S and O atoms in the heteroaryl group is not more than 2. Insome embodiments, the total number of S and O atoms in heteroaryl groupis not more than 1. Unless otherwise indicated, heteroaryl groups may bebound to the parent structure by a carbon or nitrogen atom, as valencypermits. For example, “pyridyl” includes 2-pyridyl, 3-pyridyl and4-pyridyl groups, and “pyrrolyl” includes 1-pyrrolyl, 2-pyrrolyl and3-pyrrolyl groups. When nitrogen is present in a heteroaryl ring, itmay, where the nature of the adjacent atoms and groups permits, exist inan oxidized state (i.e., N⁺—O⁻). Additionally, when sulfur is present ina heteroaryl ring, it may, where the nature of the adjacent atoms andgroups permits, exist in an oxidized state (i.e., S⁺—O⁻ or SO₂).Heteroaryl groups may be monocyclic or polycyclic (e.g., bicyclic,tricyclic).

In some instances, a heteroaryl group is monocyclic. Examples includepyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole,1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole,oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole),thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine,pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

In some instances, both rings of a polycyclic heteroaryl group arearomatic. Examples include indole, isoindole, indazole, benzoimidazole,benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole,benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole,1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine,3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine,1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine,1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine,1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine,3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine,1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine,1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine,furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine,[1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine,oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine,[1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine,oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine,[1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine,oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine,[1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine,thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine,[1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine,thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine,[1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine,thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine,[1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine,thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine,[1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline,quinazoline, quinoxaline, phthalazine, naphthyridine (e.g.,1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine,1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine),imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole,1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole.

In other instances, polycyclic heteroaryl groups may include anon-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclicheteroaryl group is bound to the parent structure via an atom in thearomatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-ylgroup (wherein the moiety is bound to the parent structure via anaromatic carbon atom) is considered a heteroaryl group, while4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound tothe parent structure via a non-aromatic carbon atom) is not considered aheteroaryl group. Examples of polycyclic heteroaryl groups consisting ofa heteroaryl ring fused to a non-aromatic ring are described below.

“Heterocycloalkyl” indicates a non-aromatic, fully saturated ring havingthe indicated number of atoms (e.g., 3 to 10, or 3 to 7, memberedheterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4heteroatoms) selected from N, O and S and with the remaining ring atomsbeing carbon. Heterocycloalkyl groups may be monocyclic or polycyclic(e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups includeoxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl andthiomorpholinyl. When nitrogen is present in a heterocycloalkyl ring, itmay, where the nature of the adjacent atoms and groups permits, exist inan oxidized state (i.e., N⁺—O⁻). Examples include piperidinyl N-oxideand morpholinyl-N-oxide. Additionally, when sulfur is present in aheterocycloalkyl ring, it may, where the nature of the adjacent atomsand groups permits, exist in an oxidized state (i.e., S⁺—O⁻ or —SO₂—).Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide.In addition, one ring of a polycyclic heterocycloalkyl group may bearomatic (e.g., aryl or heteroaryl), provided the polycyclicheterocycloalkyl group is bound to the parent structure via anon-aromatic carbon or nitrogen atom. For example, a1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moiety is bound tothe parent structure via a non-aromatic nitrogen atom) is considered aheterocycloalkyl group, while 1,2,3,4-tetrahydroquinolin-8-yl group(wherein the moiety is bound to the parent structure via an aromaticcarbon atom) is not considered a heterocycloalkyl group. Examples ofpolycyclic heterocycloalkyl groups consisting of a heterocycloalkylgroup fused to an aromatic ring are described below.

“Heterocycloalkenyl” indicates a non-aromatic ring having the indicatednumber of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl)made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms)selected from N, O and S and with the remaining ring atoms being carbon,and at least one double bond derived by the removal of one molecule ofhydrogen from adjacent carbon atoms, adjacent nitrogen atoms, oradjacent carbon and nitrogen atoms of the correspondingheterocycloalkyl. Heterocycloalkenyl groups may be monocyclic orpolycyclic (e.g., bicyclic, tricyclic). When nitrogen is present in aheterocycloalkenyl ring, it may, where the nature of the adjacent atomsand groups permits, exist in an oxidized state (i.e., N⁺—O⁻).Additionally, when sulfur is present in a heterocycloalkenyl ring, itmay, where the nature of the adjacent atoms and groups permits, exist inan oxidized state (i.e., S⁺—O⁻ or —SO₂—). Examples of heterocycloalkenylgroups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl,2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl,2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl,2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g.,2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl,dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl),tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl,1,2,3,6-tetrahydropyridinyl) and dihydropyridine (e.g.,1,2-dihydropyridine, 1,4-dihydropyridine). In addition, one ring of apolycyclic heterocycloalkenyl group may be aromatic (e.g., aryl orheteroaryl), provided the polycyclic heterocycloalkenyl group is boundto the parent structure via a non-aromatic carbon or nitrogen atom. Forexample, a 1,2-dihydroquinolin-1-yl group (wherein the moiety is boundto the parent structure via a non-aromatic nitrogen atom) is considereda heterocycloalkenyl group, while 1,2-dihydroquinolin-8-yl group(wherein the moiety is bound to the parent structure via an aromaticcarbon atom) is not considered a heterocycloalkenyl group. Examples ofpolycyclic heterocycloalkenyl groups consisting of a heterocycloalkenylgroup fused to an aromatic ring are described below.

Examples of polycyclic rings consisting of an aromatic ring (e.g., arylor heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl,2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl,benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl,indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl,2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydrobenzofuranyl,1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl,2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl,2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl,1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl,2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl,4,5,6,7-tetrahydrobenzo[d]thiazolyl,5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one,indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one,1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one,benzofuran-3(2H)-one, isobenzofuran-1(3H)-one,benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)-one,benzo[d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one,benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one,benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one,benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one,1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one,quinazolin-4(3H)-one, quinazoline-2,4(1H,3H)-dione,quinoxalin-2(1H)-one, quinoxaline-2,3(1H,4H)-dione, cinnolin-4(3H)-one,pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one,pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one,1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one,1H-pyrrolo[2,3-b]pyridin-2(3H)-one,1,2-dihydropyrazolo[3,4-d]thiazol-3-one and4,5-dihydropyrrolo[3,4-d]thiazol-6-one. As discussed herein, whethereach ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl group is determined by the atomthrough which the moiety is bound to the parent structure.

“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space. “Enantiomers” are stereoisomers that arenon-superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The symbol “(±)” may be used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. A “meso compound” or “meso isomer” is anon-optically active member of a set of stereoisomers. Meso isomerscontain two or more stereocenters but are not chiral (i.e., a plane ofsymmetry exists within the molecule). The absolute stereochemistry isspecified according to the Cahn-Ingold-Prelog R—S system. When acompound is a pure enantiomer the stereochemistry at each chiral carboncan be specified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdisclosed and/or described herein contain one or more asymmetric centersand can thus give rise to enantiomers, diastereomers, meso isomers andother stereoisomeric forms. Unless otherwise indicated, compoundsdisclosed and/or described herein include all such possible enantiomers,diastereomers, meso isomers and other stereoisomeric forms, includingracemic mixtures, optically pure forms and intermediate mixtures.Enantiomers, diastereomers, meso isomers and other stereoisomeric formscan be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques. Unless specified otherwise, when thecompounds disclosed and/or described herein contain olefinic doublebonds or other centers of geometric asymmetry, it is intended that thecompounds include both E and Z isomers.

The stereochemistry depicted in the structures of cyclic meso compoundsis not absolute; rather the stereochemistry is intended to indicate thepositioning of the substituents relative to one another, e.g., cis ortrans.

For example,

is intended to designate a compound wherein the fluorine and pyridylsubstituents on the cyclobutyl ring are in a cis configuration to oneanother, while

is intended to designate a compound wherein the fluorine and pyridylsubstituents on the cyclobutyl ring are in a trans configuration to oneanother.

When a compound can exist as one or more meso isomers, all possible mesoisomers are intended to be included. For example, the compound3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)pyridazin-3-yl]benzenecarbonitrileis intended to include both cis and trans meso isomers:

and mixtures thereof. Unless otherwise indicated, compounds disclosedand/or described herein include all possible meso isomers and mixturesthereof.

“Tautomers” are structurally distinct isomers that interconvert bytautomerization. Tautomerization is a form of isomerization and includesprototropic or proton-shift tautomerization, which is considered asubset of acid-base chemistry. Prototropic tautomerization orproton-shift tautomerization involves the migration of a protonaccompanied by changes in bond order, often the interchange of a singlebond with an adjacent double bond. Where tautomerization is possible(e.g. in solution), a chemical equilibrium of tautomers can be reached.An example of tautomerization is keto-enol tautomerization. A specificexample of keto-enol tautomerization is the interconverision ofpentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Anotherexample of tautomerization is phenol-keto tautomerization. A specificexample of phenol-keto tautomerization is the interconversion ofpyridin-4-ol and pyridin-4(1H)-one tautomers. When the compoundsdescribed herein contain moieties capable of tautomerization, and unlessspecified otherwise, it is intended that the compounds include allpossible tautomers.

“Protecting group” has the meaning conventionally associated with it inorganic synthesis, i.e., a group that selectively blocks one or morereactive sites in a multifunctional compound such that a chemicalreaction can be carried out selectively on another unprotected reactivesite, and such that the group can readily be removed after the selectivereaction is complete. A variety of protecting groups are disclosed, forexample, in T. H. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999). Forexample, a “hydroxy protected form” contains at least one hydroxy groupprotected with a hydroxy protecting group. Likewise, amines and otherreactive groups may similarly be protected.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds describedherein and are not biologically or otherwise undesirable. Examples ofpharmaceutically acceptable salts can be found in Berge et al.,Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1),1-19. In many cases, the compounds described herein are capable offorming acid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. Pharmaceutically acceptableacid addition salts can be formed with inorganic acids and organicacids. Inorganic acids from which salts can be derived include, forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, and phosphoric acid. Organic acids from which salts can be derivedinclude, for example, acetic acid, propionic acid, glycolic acid,pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonicacid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acidand salicylic acid. Pharmaceutically acceptable base addition salts canbe formed with inorganic and organic bases. Inorganic bases from whichsalts can be derived include, for example, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, andaluminum. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines; substituted aminesincluding naturally occurring substituted amines; cyclic amines; andbasic ion exchange resins. Examples of organic bases includeisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. In some embodiments, thepharmaceutically acceptable base addition salt is chosen from ammonium,potassium, sodium, calcium, and magnesium salts.

If the compound described herein is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acid salt.Conversely, if the compound is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds (see,e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences,January 1977, 66(1), 1-19). Those skilled in the art will recognizevarious synthetic methodologies that may be used to preparepharmaceutically acceptable addition salts.

A “solvate” is formed by the interaction of a solvent and a compound.Suitable solvents include, for example, water and alcohols (e.g.,ethanol). Solvates include hydrates having any ratio of compound towater, such as monohydrates, dihydrates and hemi-hydrates.

A “chelate” is formed by the coordination of a compound to a metal ionat two (or more) points. The term “compound” is intended to includechelates of compounds. Similarly, “salts” includes chelates of salts and“solvates” includes chelates of solvates.

A “non-covalent complex” is formed by the interaction of a compound andanother molecule wherein a covalent bond is not formed between thecompound and the molecule. For example, complexation can occur throughvan der Waals interactions, hydrogen bonding, and electrostaticinteractions (also called ionic bonding). Such non-covalent complexesare included in the term “compound”.

The term “prodrug” refers to a substance administered in an inactive orless active form that is then transformed (e.g., by metabolic processingof the prodrug in the body) into an active compound. The rationalebehind administering a prodrug is to optimize absorption, distribution,metabolism, and/or excretion of the drug. Prodrugs may be obtained bymaking a derivative of an active compound (e.g., a compound of Formula Ior another compound disclosed and/or described herein) that will undergoa transformation under the conditions of use (e.g., within the body) toform the active compound. The transformation of the prodrug to theactive compound may proceed spontaneously (e.g., by way of a hydrolysisreaction) or it can be catalyzed or induced by another agent (e.g., anenzyme, light, acid or base, and/or temperature). The agent may beendogenous to the conditions of use (e.g., an enzyme present in thecells to which the prodrug is administered, or the acidic conditions ofthe stomach) or the agent may be supplied exogenously. Prodrugs can beobtained by converting one or more functional groups in the activecompound into another functional group, which is then converted back tothe original functional group when administered to the body. Forexample, a hydroxyl functional group can be converted to a sulfonate,phosphate, ester or carbonate group, which in turn can be hydrolyzed invivo back to the hydroxyl group. Similarly, an amino functional groupcan be converted, for example, into an amide, carbamate, imine, urea,phosphenyl, phosphoryl or sulfenyl functional group, which can behydrolyzed in vivo back to the amino group. A carboxyl functional groupcan be converted, for example, into an ester (including silyl esters andthioesters), amide or hydrazide functional group, which can behydrolyzed in vivo back to the carboxyl group. Examples of prodrugsinclude, but are not limited to, phosphate, acetate, formate andbenzoate derivatives of functional groups (such as alcohol or aminegroups) present in the compounds of Formula I and other compoundsdisclosed and/or described herein.

The compounds disclosed and/or described herein can be enriched isotopicforms, e.g., enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or ¹⁴C. Inone embodiment, the compound contains at least one deuterium atom. Suchdeuterated forms can be made, for example, by the procedure described inU.S. Pat. Nos. 5,846,514 and 6,334,997. Such deuterated compounds mayimprove the efficacy and increase the duration of action of compoundsdisclosed and/or described herein. Deuterium substituted compounds canbe synthesized using various methods, such as those described in: Dean,D., Recent Advances in the Synthesis and Applications of RadiolabeledCompounds for Drug Discovery and Development, Curr. Pharm. Des., 2000;6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds viaOrganometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; andEvans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem.,1981, 64(1-2), 9-32.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in pharmaceutical compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the pharmaceutical compositions.

The term “active agent” is used to indicate a compound that hasbiological activity. In some embodiments, an “active agent” is acompound having therapeutic utility. In some embodiments, the compoundenhances at least one aspect of skeletal muscle function or activity,such as power output, skeletal muscle force, skeletal muscle endurance,oxygen consumption, efficiency, and/or calcium sensitivity. In someembodiments, an active agent is a compound of Formula I, or apharmaceutically acceptable salt thereof.

The terms “patient” and “subject” refer to an animal, such as a mammalbird or fish. In some embodiments, the patient or subject is a mammal.Mammals include, for example, mice, rats, dogs, cats, pigs, sheep,horses, cows and humans. In some embodiments, the patient or subject isa human, for example a human that has been or will be the object oftreatment, observation or experiment. The compounds, compositions andmethods described herein can be useful in both human therapy andveterinary applications.

As used herein, “skeletal muscle” includes skeletal muscle tissue aswell as components thereof, such as skeletal muscle fibers, themyofibrils comprising the skeletal muscle fibers, the skeletal sarcomerewhich comprises the myofibrils, and the various components of theskeletal sarcomere described herein, including skeletal myosin, actin,tropomyosin, troponin C, troponin I, troponin T and fragments andisoforms thereof. In some embodiments, “skeletal muscle” includes fastskeletal muscle tissue as well as components thereof, such as fastskeletal muscle fibers, the myofibrils comprising the fast skeletalmuscle fibers, the fast skeletal sarcomere which comprises themyofibrils, and the various components of the fast skeletal sarcomeredescribed herein, including fast keletal myosin, actin, tropomyosin,troponin C, troponin I, troponin T and fragments and isoforms thereof.Skeletal muscle does not include cardiac muscle or a combination ofsarcomeric components that occurs in such combination in its entirety incardiac muscle.

As used herein, the term “therapeutic” refers to the ability to modulatethe contractility of fast skeletal muscle. As used herein, “modulation”(and related terms, such as “modulate”, “modulated”, “modulating”)refers to a change in function or efficiency of one or more componentsof the fast skeletal muscle sarcomere, including myosin, actin,tropomyosin, troponin C, troponin I, and troponin T from fast skeletalmuscle, including fragments and isoforms thereof, as a direct orindirect response to the presence of a compound described herein,relative to the activity of the fast skeletal sarcomere in the absenceof the compound. The change may be an increase in activity(potentiation) or a decrease in activity (inhibition), and may be due tothe direct interaction of the compound with the sarcomere, or due to theinteraction of the compound with one or more other factors that in turnaffect the sarcomere or one or more of its components. In someembodiments, modulation is a potentiation of function or efficiency ofone or more components of the fast skeletal muscle sarcomere, includingmyosin, actin, tropomyosin, troponin C, troponin I, and troponin T fromfast skeletal muscle, including fragments and isoforms thereof.Modulation may be mediated by any mechanism and at any physiologicallevel, for example, through sensitization of the fast skeletal sarcomereto contraction at lower Ca²⁺ concentrations. As used herein,“efficiency” or “muscle efficiency” means the ratio of mechanical workoutput to the total metabolic cost.

The term “therapeutically effective amount” or “effective amount” refersto that amount of a compound disclosed and/or described herein that issufficient to affect treatment, as defined herein, when administered toa patient in need of such treatment. A therapeutically effective amountof a compound may be an amount sufficient to treat a disease responsiveto modulation of fast skeletal muscle. The therapeutically effectiveamount will vary depending upon, for example, the subject and diseasecondition being treated, the weight and age of the subject, the severityof the disease condition, the particular compound, the dosing regimen tobe followed, timing of administration, the manner of administration, allof which can readily be determined by one of ordinary skill in the art.The therapeutically effective amount may be ascertained experimentally,for example by assaying blood concentration of the chemical entity, ortheoretically, by calculating bioavailability.

“Treatment” (and related terms, such as “treat”, “treated”, “treating”)includes one or more of: preventing a disease or disorder (i.e., causingthe clinical symptoms of the disease or disorder not to develop);inhibiting a disease or disorder; slowing or arresting the developmentof clinical symptoms of a disease or disorder; and/or relieving adisease or disorder (i.e., causing relief from or regression of clinicalsymptoms). The term encompasses situations where the disease or disorderis already being experienced by a patient, as well as situations wherethe disease or disorder is not currently being experienced but isexpected to arise. The term covers both complete and partial reductionor prevention of the condition or disorder, and complete or partialreduction of clinical symptoms of a disease or disorder. Thus, compoundsdescribed and/or disclosed herein may prevent an existing disease ordisorder from worsening, assist in the management of the disease ordisorder, or reduce or eliminate the disease or disorder. When used in aprophylactic manner, the compounds disclosed and/or described herein mayprevent a disease or disorder from developing or lessen the extent of adisease or disorder that may develop.

As used herein, “power output” of a muscle means work/cycle time and maybe scaled up from PoLo/cycle time units based on the properties of themuscle. Power output may be modulated by changing, for example,activating parameters during cyclical length changes, including timingof activation (phase of activation) and the period of activation (dutycycle.)

“ATPase” refers to an enzyme that hydrolyzes ATP. ATPases includeproteins comprising molecular motors such as the myosins.

As used herein, “selective binding” or “selectively binding” refers topreferential binding to a target protein in one type of muscle or musclefiber as opposed to other types. For example, a compound selectivelybinds to fast skeletal troponin C if the compound preferentially bindstroponin C in the troponin complex of a fast skeletal muscle fiber orsarcomere in comparison with troponin C in the troponin complex of aslow muscle fiber or sarcomere or with troponin C in the troponincomplex of a cardiac sarcomere.

Provided is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from hydrogen, halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C(O)OR^(a), C(O)NR^(b)R^(c), OR^(a), NR^(b)R^(c), C₆₋₁₀ aryl and 5-10membered heteroaryl;

R² is selected from C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, 5-10membered heteroaryl and NR^(b)R^(c), wherein each of the C₃₋₈cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl and 5-10 membered heteroarylgroups is optionally substituted with 1, 2, 3, 4 or 5 substituentsselected from halogen, CN, oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,(CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 membered heterocycloalkyl,(CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 membered heteroaryl groups isoptionally substituted with 1, 2, 3, 4 or 5 R^(f) substituents;

R³ is selected from hydrogen, halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C(O)OR^(a), C(O)NR^(b)R^(c), OR^(a), NR^(b)R^(c), C₆₋₁₀ aryl and 5-10membered heteroaryl;

R⁴ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)R^(a),C(O)OR^(a), C(O)NR^(b)R^(c) and SO₂R^(a);

R⁵ and R⁶ are each independently selected from hydrogen, halogen, C₁₋₆alkyl and C₁₋₆ haloalkyl;

or alternatively, R⁵ and R⁶ together with the carbon atom to which theyare bound form C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl or 3-8 membered heterocycloalkenyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN,oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a),C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆alkyl and C₁₋₆ haloalkyl;

R⁷ is selected from C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl and 5-10membered heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents;

R⁸ and R⁹, at each occurrence, are each independently selected fromhydrogen, halogen and C₁₋₆ alkyl;

X is selected from a bond, —(CH₂)_(p)—, —(CH₂)_(p)C(O)(CH₂)_(q)—,—(CH₂)_(p)O(CH₂)_(q)—, —(CH₂)_(p)S(CH₂)_(q)—,—(CH₂)_(p)NR^(d)(CH₂)_(q)—, —(CH₂)_(p)C(O)O(CH₂)_(q)—,—(CH₂)_(p)OC(O)(CH₂)_(q)—, —(CH₂)_(p)NR^(d)C(O)(CH₂)_(q)—,—(CH₂)_(p)C(O)NR^(d)(CH₂)_(q)—, —(CH₂)_(p)NR^(d)C(O)NR^(d)(CH₂)_(q)—,—(CH₂)_(p)NR^(d)SO₂(CH₂)_(q)—, and —(CH₂)_(p)SO₂NR^(d)(CH₂)_(q)—;

or alternatively, X, R² and R³, together with the carbon atoms to whichthey are bound, form a 5-6 membered ring optionally containing one ormore heteroatoms selected from oxygen nitrogen and sulfur, andoptionally containing one or more double bonds, and optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents;

R^(a), at each occurrence, is independently selected from hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents;

R^(b) and R^(c), at each occurrence, are each independently selectedfrom hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl, 5-10 memberedheteroaryl, C(O)R^(g), C(O)OR^(g), C(O)NR^(i)R^(j) and SO₂R^(g), whereineach of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents;

R^(d), at each occurrence, is independently selected from hydrogen and

C₁₋₆ alkyl;

R^(e), at each occurrence, is independently selected from hydrogen, CN,OH, C₁₋₆ alkoxy, C₁₋₆ alkyl and C₁₋₆ haloalkyl;

R^(f), at each occurrence, is independently selected from halogen, CN,OR^(h), OC(O)R^(h), OC(O)OR^(h), OC(O)NR^(i)R^(j), NR^(i)R^(j),NR^(d)C(O)R^(h), NR^(d)C(O)OR^(h), NR^(d)C(O)NR^(i)R^(j),NR^(d)C(O)C(O)NR^(i)R^(j), NR^(d)C(S)R^(h), NR^(d)C(S)OR^(h),NR^(d)C(S)NR^(i)R^(j), NR^(d)C(NR^(e))NR^(i)R^(j), NR^(d)S(O)R^(h),NR^(d)SO₂R^(h), NR^(d)SO₂NR^(i)R^(j), C(O)R^(h), C(O)OR^(h),C(O)NR^(i)R^(j), C(S)R^(h), C(S)OR^(h), C(S)NR^(i)R^(j),C(NR^(e))NR^(i)R^(j), SR^(h), S(O)R^(h), SO₂R^(h), SO₂NR^(i)R^(j), C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(k)substituents;

or two R^(f) substituents bound to a single carbon atom, together withthe carbon atom to which they are both bound, form a group selected fromcarbonyl, C₃₋₈ cycloalkyl and 3-8 membered heterocycloalkyl;

R^(g), at each occurrence, is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, phenyl, naphthyl, and C₇₋₁₁ aralkyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN,OH, C₁₋₆ alkoxy, C₁₋₆ alkyl and C₁₋₆ haloalkyl;

R^(h), at each occurrence, is independently selected from hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,cycloalkyl, cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(k)substituents;

R^(i) and R^(j), at each occurrence, are each independently selectedfrom hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl, 5-10 memberedheteroaryl, C(O)R^(g), and C(O)OR⁹, wherein each of the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, OH, C₁₋₆ alkoxy, C₁₋₆ alkyl andC₁₋₆ haloalkyl;

R^(k), at each occurrence, is independently selected from halogen, CN,OH, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, NHC(O)C₁₋₆ alkyl,NHC(O)C₇₋₁₁ aralkyl, NHC(O)OC₁₋₆ alkyl, NHC(O)OC₇₋₁₁ aralkyl, OC(O)C₁₋₆alkyl, OC(O)C₇₋₁₁ aralkyl, OC(O)OC₁₋₆ alkyl, OC(O)OC₇₋₁₁ aralkyl,C(O)C₁₋₆ alkyl, C(O)C₇₋₁₁ aralkyl, C(O)OC₁₋₆ alkyl, C(O)OC₇₋₁₁ aralkyl,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein eachC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₇₋₁₁ aralkyl substituent isoptionally substituted with 1, 2 or 3 substituents selected from OH,C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, NHC(O)C₁₋₆ alkyl,NHC(O)C₇₋₁₁ aralkyl, NHC(O)OC₁₋₆ alkyl, and NHC(O)OC₇₋₁₁ aralkyl;

or two R^(k) substituents bound to a single carbon atom, together withthe carbon atom to which they are both bound, form a carbonyl group;

m is 0, 1 or 2;

n, at each occurrence, independently is 0, 1 or 2;

p is 0, 1 or 2; and

q is 0, 1 or 2.

In some embodiments of compounds of Formula I, when m is 1 and R⁵ and R⁶are each methyl, then R⁷ is not piperidinyl or morpholino. In someembodiments of compounds of Formula I, when m is 1, X is a bond and R²is optionally substituted phenyl, then R⁷ is not piperidinyl ormorpholino. In some embodiments, the compound of Formula I is not6-(4-chlorophenyl)-5-methyl-N-(2-methyl-2-(piperidin-1-yl)propyl)pyridazin-3-amine,N-(2-methyl-2-(piperidin-1-yl)propyl)-6-phenyl-5-propylpyridazin-3-amineor N-(2-methyl-2-morpholinopropyl)-6-phenyl-5-propylpyridazin-3-amine.

In some embodiments of compounds of Formula I, m is 0, i.e., a compoundof Formula II, or a pharmaceutically acceptable salt thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and X are as defined herein.

In some embodiments of compounds of Formula I, m is 1, i.e., a compoundof Formula III, or a pharmaceutically acceptable salt thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and X are as defined herein.

In some embodiments of compounds of Formula I, II or III, one of R⁵ andR⁶ is hydrogen and the other is C₁₋₆ alkyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶ areeach independently C₁₋₆ alkyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶ areeach methyl.

In some embodiments, the compounds are of Formula IV(a) or IV(b), or apharmaceutically acceptable salt thereof:

wherein R¹, R², R³, R⁴, R⁷, R⁸, R⁹ and X are as defined herein.

In some embodiments of compounds of Formula IV(b), R⁷ is not piperidinylor morpholinyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶together with the carbon atom to which they are bound form C₃₋₈cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl or 3-8membered heterocycloalkenyl, each optionally substituted with 1, 2, 3, 4or 5 substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶,together with the carbon to which they are bound, form C₃₋₆ cycloalkyloptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalogen, CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c),C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a),SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶,together with the carbon to which they are bound, form cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR^(a),OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a),C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl andC₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶,together with the carbon to which they are bound, form cyclobutyloptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalogen, CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c),C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a),SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶,together with the carbon to which they are bound, form cyclobutylsubstituted with one substituent selected from halogen, CN, oxo, OR^(a),OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a),C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl andC₁₋₆ haloalkyl, wherein the substituent and R⁷ are in a transconfiguration with respect to one another on the cyclobutyl ring.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶,together with the carbon to which they are bound, form cyclobutylsubstituted with one substituent selected from halogen, CN, oxo, OR^(a),OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a),C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl andC₁₋₆ haloalkyl, wherein the substituent and R⁷ are in a cisconfiguration with respect to one another on the cyclobutyl ring.

In some embodiments, the compounds are of Formula V(a) or V(b), or apharmaceutically acceptable salt thereof:

wherein R^(m) and R^(n) are each independently selected from hydrogen,halogen and C₁₋₆ alkyl, and R¹, R², R³, R⁴, R⁷, R⁸, R⁹ and X are asdefined herein.

In some embodiments of compounds of Formula V(a) or V(b), R^(m) andR^(n) are each hydrogen.

In some embodiments compounds of Formula V(a) or V(b), R^(m) and R^(n)are each halogen.

In some embodiments compounds of Formula V(a) or V(b), R^(m) and R^(n)are each fluorine.

In some embodiments compounds of Formula V(a) or V(b), one of R^(m) andR^(n) is hydrogen and the other is halogen. In some embodiments of suchcompounds, the halogen and R⁷ are in a trans configuration with respectto one another on the cyclobutyl ring. In some embodiments of suchcompounds, the halogen and R⁷ are in a cis configuration with respect toone another on the cyclobutyl ring.

In some embodiments compounds of Formula V(a) or V(b), one of R^(m) andR^(n) is hydrogen and the other is fluorine. In some embodiments of suchcompounds, the fluorine and R⁷ are in a trans configuration with respectto one another on the cyclobutyl ring. In some embodiments of suchcompounds, the fluorine and R⁷ are in a cis configuration with respectto one another on the cyclobutyl ring.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶,together with the carbon atom to which they are bound, form 3-6 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,4 or 5 substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶,together with the carbon atom to which they are bound, form aziridine,azetidine, pyrrolidine, oxirane, oxetane or tetrahydrofuran, each ofwhich is optionally substituted with 1, 2, 3, 4 or 5 substituentsselected from halogen, CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a),NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶ areeach independently C₁₋₆ alkyl, or R⁵ and R⁶ together with the carbonatom to which they are bound form C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl,3-8 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl, eachoptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalogen, CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c),C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a),SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶ areeach methyl, or R⁵ and R⁶ together with the carbon atom to which theyare bound form C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl or 3-8 membered heterocycloalkenyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN,oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a),C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶ areeach independently C₁₋₆ alkyl, or R⁵ and R⁶, together with the carbon towhich they are bound, form cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶ areeach methyl, or R⁵ and R⁶, together with the carbon to which they arebound, form cyclobutyl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a) or V(b), R⁷ is selected from C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl,3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, each optionally substituted with 1,2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR^(a),OC(O)R^(a), OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, III or IV(b), when R⁵ andR⁶ are each methyl, R⁷ is not piperidinyl or morpholinyl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a) or V(b), R⁷ is phenyl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments, the compounds are of Formula VI, or apharmaceutically acceptable salt thereof:

wherein r is 0, 1, 2, 3 or 4, and R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R^(f),X and m are as defined herein.

In some embodiments, the compounds are of Formula VII(a) or VII(b), or apharmaceutically acceptable salt thereof:

wherein r is 0, 1, 2, 3 or 4, and R¹, R², R³, R⁴, R⁸, R⁹, R^(f) and Xare as defined herein.

In some embodiments, the compounds are of Formula VIII(a) or VIII(b), ora pharmaceutically acceptable salt thereof:

wherein R^(m) and R^(n) are each independently selected from hydrogen,halogen and C₁₋₆ alkyl; r is 0, 1, 2, 3 or 4; and R¹, R², R³, R⁴, R⁸,R⁹, R^(f) and X are as defined herein.

In some embodiments of compounds of Formula VIII(a) or VIII(b), R^(m)and R^(n) are each hydrogen.

In some embodiments compounds of Formula VIII(a) or VIII(b), R^(m) andR^(n) are each halogen.

In some embodiments compounds of Formula VIII(a) or VIII(b), R^(m) andR^(n) are each fluorine.

In some embodiments compounds of Formula VIII(a) or VIII(b), one ofR^(m) and R^(n) is hydrogen and the other is halogen. In someembodiments of such compounds, the halogen and the phenyl ring are in atrans configuration with respect to one another on the cyclobutyl ring.In some embodiments of such compounds, the halogen and the phenyl ringare in a cis configuration with respect to one another on the cyclobutylring.

In some embodiments compounds of Formula VIII(a) or VIII(b), one ofR^(m) and R^(n) is hydrogen and the other is fluorine. In someembodiments of such compounds, the fluorine and the phenyl ring are in atrans configuration with respect to one another on the cyclobutyl ring.In some embodiments of such compounds, the fluorine and the phenyl ringare in a cis configuration with respect to one another on the cyclobutylring.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a) or V(b), R⁷ is selected from phenyl, 2-fluorophenyl,3-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 2-methylphenyl, 3-methylphenyl, 2,4-dimethylphenyl,3,4-dimethylphenyl, 3,5-dimethylphenyl, 2-(hydroxymethyl)phenyl,3-(hydroxymethyl)phenyl, 4-(hydroxymethyl)phenyl, 2-(aminomethyl)phenyl,3-(aminomethyl)phenyl, 4-(aminomethyl)phenyl, 2-phenol, 3-phenol,4-phenol, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl,4-difluoromethoxyphenyl, 2-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-cyanophenyl,3-cyanophenyl, 4-cyanophenyl, 2-benzamine, 3-benzamide, 4-benzamide,N-methyl-2-benzamine, N-methyl-3-benzamide, N-methyl-4-benzamide,N,N-dimethyl-2-benzamine, N,N-dimethyl-3-benzamide, andN,N-dimethyl-4-benzamide.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a) or V(b), R⁷ is 5-10 membered heteroaryl optionally substituted with1, 2, 3, 4 or 5 substituents selected from halogen, ON, oxo, OR^(a),OC(O)R^(a), OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a) or V(b), R⁷ is pyridyl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, ON, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a) or V(b), R⁷ is selected from 2-pyridyl, 3-pyridyl and 4-pyridyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halogen, ON, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a),OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a), NR^(d)C(O)OR^(a),NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c), NR^(d)C(S)R^(a),NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c), NR^(d)C(NR^(e))NR^(b)R^(c),NR^(d)S(O)R^(a), NR^(d)SO₂R^(a), NR^(d)SO₂NR^(b)R^(c), C(O)R^(a),C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a), C(S)OR^(a), C(S)NR^(b)R^(c),C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 memberedheterocycloalkenyl, phenyl, naphthyl, C₇₋₁₁ aralkyl, and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents.

In some embodiments, the compounds are of Formula IX, or apharmaceutically acceptable salt thereof:

wherein r is 0, 1, 2, 3 or 4, and R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R^(f),X and m are as defined herein.

In some embodiments, the compounds are of Formula X(a) or X(b), or apharmaceutically acceptable salt thereof:

wherein r is 0, 1, 2, 3 or 4, and R¹, R², R³, R⁴, R⁸, R⁹, R^(f) and Xare as defined herein.

In some embodiments, the compounds are of Formula XI(a) or XI(b), or apharmaceutically acceptable salt thereof:

wherein R^(m) and R^(n) are each independently selected from hydrogen,halogen and C₁₋₆ alkyl; r is 0, 1, 2, 3 or 4; and R¹, R², R³, R⁴, R⁸,R⁹, R^(f) and X are as defined herein.

In some embodiments of compounds of Formula XI(a) or XI(b), R^(m) andR^(n) are each hydrogen.

In some embodiments compounds of Formula XI(a) or XI(b), R^(m) and R^(n)are each halogen.

In some embodiments compounds of Formula XI(a) or XI(b), R^(m) and R^(n)are each fluorine.

In some embodiments compounds of Formula XI(a) or XI(b), one of R^(m)and R^(n) is hydrogen and the other is halogen. In some embodiments ofsuch compounds, the halogen and the pyridyl ring are in a transconfiguration with respect to one another on the cyclobutyl ring. Insome embodiments of such compounds, the halogen and the pyridyl ring arein a cis configuration with respect to one another on the cyclobutylring.

In some embodiments compounds of Formula XI(a) or XI(b), one of R^(m)and R^(n) is hydrogen and the other is fluorine. In some embodiments ofsuch compounds, the fluorine and the pyridyl ring are in a transconfiguration with respect to one another on the cyclobutyl ring. Insome embodiments of such compounds, the fluorine and the pyridyl ringare in a cis configuration with respect to one another on the cyclobutylring.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a) or V(b), R⁷ is selected from pyrid-2-yl, 3-fluoro-pyrid-2-yl,4-fluoro-pyrid-2-yl, 5-fluoro-pyrid-2-yl, 6-fluoro-pyrid-2-yl,3-chloro-pyrid-2-yl, 4-chloro-pyrid-2-yl, 5-chloro-pyrid-2-yl,6-chloro-pyrid-2-yl, 3-cyano-pyrid-2-yl, 4-cyano-pyrid-2-yl,5-cyano-pyrid-2-yl, 6-cyano-pyrid-2-yl, 3-methyl-pyrid-2-yl,4-methyl-pyrid-2-yl, 5-methyl-pyrid-2-yl, 6-methyl-pyrid-2-yl,3-difluoromethyl-pyrid-2-yl, 4-difluoromethyl-pyrid-2-yl,5-difluoromethyl-pyrid-2-yl, 6-difluoromethyl-pyrid-2-yl,3-trifluoromethyl-pyrid-2-yl, 4-trifluoromethyl-pyrid-2-yl,5-trifluoromethyl-pyrid-2-yl, 6-trifluoromethyl-pyrid-2-yl,3-hydroxymethyl-pyrid-2-yl, 4-hydroxymethyl-pyrid-2-yl,5-hydroxymethyl-pyrid-2-yl, 6-hydroxymethyl-pyrid-2-yl,3-aminomethyl-pyrid-2-yl, 4-aminomethyl-pyrid-2-yl,5-aminomethyl-pyrid-2-yl, 6-aminomethyl-pyrid-2-yl,3-hydroxy-pyrid-2-yl, 4-hydroxy-pyrid-2-yl, 5-hydroxy-pyrid-2-yl,6-hydroxy-pyrid-2-yl, 3-methoxy-pyrid-2-yl, 4-methoxy-pyrid-2-yl,5-methoxy-pyrid-2-yl, 6-methoxy-pyrid-2-yl,3-difluoromethoxy-pyrid-2-yl, 4-difluoromethoxy-pyrid-2-yl,5-difluoromethoxy-pyrid-2-yl, 6-difluoromethoxy-pyrid-2-yl,3-trifluoromethoxy-pyrid-2-yl, 4-trifluoromethoxy-pyrid-2-yl,5-trifluoromethoxy-pyrid-2-yl, 6-trifluoromethoxy-pyrid-2-yl,3-methylthio-pyrid-2-yl, 4-methylthio-pyrid-2-yl,5-methylthio-pyrid-2-yl, 6-methylthio-pyrid-2-yl,3-carboxamide-pyrid-2-yl, 4-carboxamide-pyrid-2-yl,5-carboxamide-pyrid-2-yl, 6-carboxamide-pyrid-2-yl and3-fluoro-6-methyl-pyrid-2-yl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a) or V(b), R⁷ is selected from pyrid-3-yl, 2-fluoro-pyrid-3-yl,4-fluoro-pyrid-3-yl, 5-fluoro-pyrid-3-yl, 6-fluoro-pyrid-3-yl,2-chloro-pyrid-3-yl, 4-chloro-pyrid-3-yl, 5-chloro-pyrid-3-yl,6-chloro-pyrid-3-yl, 2-cyano-pyrid-3-yl, 4-cyano-pyrid-3-yl,5-cyano-pyrid-3-yl, 6-cyano-pyrid-3-yl, 2-methyl-pyrid-3-yl,4-methyl-pyrid-3-yl, 5-methyl-pyrid-3-yl, 6-methyl-pyrid-3-yl,2-difluoromethyl-pyrid-3-yl, 4-difluoromethyl-pyrid-3-yl,5-difluoromethyl-pyrid-3-yl, 6-difluoromethyl-pyrid-3-yl,2-trifluoromethyl-pyrid-3-yl, 4-trifluoromethyl-pyrid-3-yl,5-trifluoromethyl-pyrid-3-yl, 6-trifluoromethyl-pyrid-3-yl,2-hydroxymethyl-pyrid-3-yl, 4-hydroxymethyl-pyrid-3-yl,5-hydroxymethyl-pyrid-3-yl, 6-hydroxymethyl-pyrid-3-yl,2-aminomethyl-pyrid-3-yl, 4-aminomethyl-pyrid-3-yl,5-aminomethyl-pyrid-3-yl, 6-aminomethyl-pyrid-3-yl,2-hydroxy-pyrid-3-yl, 4-hydroxy-pyrid-3-yl, 5-hydroxy-pyrid-3-yl,6-hydroxy-pyrid-3-yl, 2-methoxy-pyrid-3-yl, 4-methoxy-pyrid-3-yl,5-methoxy-pyrid-3-yl, 6-methoxy-pyrid-3-yl,2-difluoromethoxy-pyrid-3-yl, 4-difluoromethoxy-pyrid-3-yl,5-difluoromethoxy-pyrid-3-yl, 6-difluoromethoxy-pyrid-3-yl,2-trifluoromethoxy-pyrid-3-yl, 4-trifluoromethoxy-pyrid-3-yl,5-trifluoromethoxy-pyrid-3-yl, 6-trifluoromethoxy-pyrid-3-yl,2-methylthio-pyrid-3-yl, 4-methylthio-pyrid-3-yl,5-methylthio-pyrid-3-yl, 6-methylthio-pyrid-3-yl,2-carboxamide-pyrid-3-yl, 4-carboxamide-pyrid-3-yl,5-carboxamide-pyrid-3-yl and 6-carboxamide-pyrid-3-yl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), X is selected from a bond, —(CH₂)_(p)—,—(CH₂)_(p)C(O)(CH₂)_(q)—, —(CH₂)_(p)O(CH₂)_(q)—, —(CH₂)_(p)S(CH₂)_(q)—,—(CH₂)_(p)NR^(d)(CH₂)_(q)—, —(CH₂)_(p)C(O)O(CH₂)_(q)—,—(CH₂)_(p)OC(O)(CH₂)_(q)—, —(CH₂)_(p)NR^(d)C(O)(CH₂)_(q)—,—(CH₂)_(p)C(O)NR^(d)(CH₂)_(q)—, —(CH₂)_(p)NR^(d)C(O)NR^(d)(CH₂)_(q)—,—(CH₂)_(p)NR^(d)SO₂(CH₂)_(q)—, and —(CH₂)_(p)SO₂NR^(d)(CH₂)_(q)—.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), X is a bond.

In some embodiments, the compound is of Formula XII(a), XII(b), XII(c),XII(d), XII(e), XII(f), XII(g), XII(h), XII(i), XII(j), XII(k), XII(l),XII(m), XII(n) or XII(o), or a pharmaceutically acceptable salt thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(f), R^(m), R^(n), m and rare as defined herein.

In some embodiments of compounds of Formula XII(c), R⁷ is notpiperidinyl or morpholinyl. In some embodiments of compounds of FormulaXII(c), when R² is optionally substituted phenyl, then R⁷ is notpiperidinyl or morpholinyl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), X is —O—.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), X is selected from —CH₂O— and —OCH₂—.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), X is —NR^(d)—.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), X is selected from —CH₂NR^(d)— and —NR^(d)CH₂—.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), X is selected from —NR^(d)C(O)— and —C(O)NR^(d)—.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), X is selected from —CH₂NR^(d)C(O)— and —C(O)NR^(d)CH₂—.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl,3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is phenyloptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalogen, CN, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a),(CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is phenylsubstituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN,(CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a),(CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)O(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents; wherein at least one substitutent is bonded at themeta position.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is phenylsubstituted with a substituent selected from (CH₂)_(n)C(O)OR^(a) and(CH₂)_(n)C(O)NR^(b)R^(c); and optionally substituted with 1, 2 or 3additional substituents selected from halogen, CN, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)O(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is phenylsubstituted with a substituent selected from C(O)OH, C(O)NH₂, C(O)OC₁₋₆alkyl, C(O)NHC₁₋₆ alkyl and C(O)N(C₁₋₆ alkyl)₂; and optionallysubstituted with 1, 2 or 3 additional substituents selected fromhalogen, C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is phenylsubstituted at the meta position with a substituent selected from(CH₂)_(n)C(O)OR^(a) and (CH₂)_(n)C(O)NR^(b)R^(c); and optionallysubstituted with 1, 2 or 3 additional substituents selected fromhalogen, CN, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a),(CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is phenylsubstituted at the meta position with a substituent selected from(CH₂)_(n)C(O)OR^(a) and (CH₂)_(n)C(O)NR^(b)R^(c), and optionallysubstituted with 1, 2 or 3 additional substituents selected fromhalogen, hydroxyl, C₁₋₆ alkoxy, CN, C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is phenylsubstituted at the meta position with a substituent selected fromC(O)OH, C(O)NH₂, C(O)OC₁₋₆ alkyl, C(O)NHC₁₋₆ alkyl and C(O)N(C₁₋₆alkyl)₂; and optionally substituted with 1, 2 or 3 additionalsubstituents selected from halogen, hydroxyl, C₁₋₆ alkoxy, CN, C₁₋₆alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is phenylsubstituted with (CH₂)_(n)NR^(d)C(O)R^(a), wherein R^(a) is C₁₋₆ alkylor 3-8 membered heterocycloalkyl, each optionally substituted with 1, 2or 3 substituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl; and optionally substituted with 1, 2or 3 additional substituents selected from halogen, CN, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is phenylsubstituted with (CH₂)_(n)NR^(d)C(O)R^(a), wherein R^(a) is selectedfrom C₁₋₆ alkyl, C₁₋₆ alkyl-OH and C₁₋₆ alkyl-NH₂, each optionallysubstituted with 1, 2 or 3 substituents selected from halogen, CN, oxo,(CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a),(CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, and (CH₂)_(n)5-10 memberedheteroaryl; and optionally substituted with 1, 2 or 3 additionalsubstituents selected from halogen, CN, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom 3-benzamide, N-methyl-3-benzamide, N,N-dimethyl-3-benzamide,4-fluoro-3-benzamide, N-methyl-4-fluoro-3-benzamide,N,N-dimethyl-4-fluoro-3-benzamide, 3-benzoic acid, methyl-3-benzoate,4-fluoro-3-benzoic acid, and methyl-4-fluoro-3-benzoate.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is 5-10membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl,thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionallysubstituted with 1, 2, 3 or 4 substituents selected from halogen, CN,oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a),(CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl,thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionallysubstituted with a substituent selected from (CH₂)_(n)C(O)OR^(a) and(CH₂)_(n)C(O)NR^(b)R^(c); and optionally substituted with 1, 2 or 3additional substituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom pyridyl, pyrimidyl, pyrazyl, pyridazyl and triazyl, each optionallysubstituted with (CH₂)_(n)C(O)NR^(b)R^(c).

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl,thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyland tetrazolyl, each optionally substituted with(CH₂)_(n)C(O)NR^(b)R^(c).

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom pyridyl, pyrimidyl, pyrazyl, pyridazyl and triazyl, each optionallysubstituted with (CH₂)_(n)C(O)NH₂.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl,thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyland tetrazolyl, each optionally substituted with (CH₂)_(n)C(O)NH₂.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl,thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionallysubstituted with (CH₂)_(n)NR^(d)C(O)R^(a), wherein R^(a) is C₁₋₆ alkylor 3-8 membered heterocycloalkyl, each optionally substituted with 1, 2or 3 substituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom pyridyl, pyrimidyl, pyrazyl, pyridazyl and triazyl, each optionallysubstituted with (CH₂)_(n)NR^(d)C(O)R^(a), wherein R^(a) is selectedfrom C₁₋₆ alkyl, C₁₋₆ alkyl-OH and C₁₋₆ alkyl-NH₂, each optionallysubstituted with 1, 2 or 3 substituents selected from halogen, CN,(CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a),(CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfuranyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl,each optionally substituted with (CH₂)_(n)NR^(d)C(O)R^(a), wherein R^(a)is selected from C₁₋₆ alkyl, C₁₋₆ alkyl-OH and C₁₋₆ alkyl-NH₂, eachoptionally substituted with 1, 2 or 3 substituents selected fromhalogen, CN, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a),(CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom indolyl, indazolyl, benzimidazolyl, benzoxazolyl andbenzoisoxazolyl, each optionally substituted with 1, 2, 3 or 4substituents selected from halogen, ON, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom 1H-indazol-6-yl, 1H-indazol-5-yl, 1H-indazol-4-yl,3-amino(1H-indazol-5-yl), 3-amino(1H-indazol-6-yl),3-amino(1H-indazol-7-yl), 1-methyl(1H-indazol-6-yl),3-methyl(1H-indazol-6-yl), 3-amino-1-methyl(1H-indazol-5-yl),3-cyano(1H-indazol-5-yl), 3-carboxamide(1H-indazol-5-yl),3-carboxamidine(1H-indazol-5-yl), 3-vinyl(1H-indazol-5-yl),3-ethyl(1H-indazol-5-yl), 3-acetamide(1H-indazol-5-yl),3-methylsulfonylamine(1H-indazol-5-yl),3-methoxycarboxamide(1H-indazol-5-yl), 3-methylamino(1H-indazol-5-yl),3-dimethylamino(1H-indazol-5-yl), 3-ethylamino(1H-indazol-5-yl),3-(2-aminoethyl)amino(1H-indazol-5-yl),3-(2-hydroxyethyl)amino(1H-indazol-5-yl),3-[(methylethyl)amino](1H-indazol-5-yl), 6-benzimidazol-5-yl,6-(2-methylbenzimidazol-5-yl), 2-aminobenzimidazol-5-yl,2-hydroxybenzimidazol-5-yl, 2-acetamidebenzimidazol-5-yl,3-aminobenzo[3,4-d]isoxazol-5-yl, 3-aminobenzo[d]isoxazol-6-yl,3-aminobenzo[d]isoxazol-7-yl, 2-methylbenzoxazol-5-yl and2-methylbenzoxazol-6-yl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom 3-6 membered heterocycloalkyl and 3-6 membered heterocycloalkenyl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom halogen, CN, oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R² is selectedfrom aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl andmorpholinyl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), R² is NR^(b)R^(c), wherein R^(b) and R^(c) are as definedherein.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), R² is NR^(b)R^(c), wherein one of R^(b) and R^(c) is hydrogenand the other is C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4 or 5R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), X is —C(O)— and R² is NR^(b)R^(c), wherein R^(b) and R^(c) areas defined herein.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), X is —C(O)— and R² is NR^(b)R^(c), wherein one of R^(b) andR^(c) is hydrogen and the other is C₁₋₆ alkyl optionally substitutedwith 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), X is —(CH₂)_(p)— and R² is NR^(b)R^(c), wherein R^(b) andR^(c) are as defined herein.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a)or XI(b), X is —(CH₂)_(p)— and R² is NR^(b)R^(c), wherein one of R^(b)and R^(c) is hydrogen and the other is C₁₋₆ alkyl optionally substitutedwith 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments, X, R² and R³, together with the carbon atoms towhich they are bound, form a 5-6 membered ring optionally containing oneor more heteroatoms selected from oxygen nitrogen and sulfur, andoptionally containing one or more double bonds, and optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments, the compound is of Formula XIII, or apharmaceutically acceptable salt thereof:

wherein A is a 5 or 6 membered ring optionally containing one or moreheteroatoms selected from oxygen nitrogen and sulfur, and optionallycontaining one or more double bonds; t is 0, 1, 2, 3 or 4; and R¹, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, R^(f) and m are as defined herein.

In some embodiments of compounds of Formula XIII, ring A together withthe pyridazine ring to which it is bound form a group selected fromcinnoline, pyrido[2,3-c]pyridazine, pyrido[3,4-c]pyridazine,pyrido[4,3-c]pyridazine, pyrido[3,2-c]pyridazine,5,6,7,8-tetrahydrocinnoline, 5,6,7,8-tetrahydropyrido[2,3-c]pyridazine,5,6,7,8-tetrahydropyrido[3,4-c]pyridazine,5,6,7,8-tetrahydropyrido[4,3-c]pyridazine,5,6,7,8-tetrahydropyrido[3,2-c]pyridazine, thieno[2,3-c]pyridazine,thiazolo[5,4-c]pyridazine, 7H-pyrrolo[2,3-c]pyridazine,7H-imidazo[4,5-c]pyridazine, thieno[3,2-c]pyridazine,thiazolo[4,5-c]pyridazine, 5H-pyrrolo[3,2-c]pyridazine,5H-imidazo[4,5-c]pyridazine, 1H-pyrazolo[4,3-c]pyridazine,1H-pyrazolo[3,4-c]pyridazine, 3H-[1,2,3]triazolo[4,5-c]pyridazine,6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine,6,7-dihydro-5H-pyrrolo[3,4-c]pyridazine,6,7-dihydro-5H-pyrrolo[3,2-c]pyridazine and6,7-dihydro-5H-cyclopenta[c]pyridazine, each optionally substituted with1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n), XII(o) or XIII, R¹ isselected from hydrogen, halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C(O)OR^(a), C(O)NR^(b)R^(c), OR^(a), NR^(b)R^(c), C₆₋₁₀ aryl and 5-10membered heteroaryl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n), XII(o) or XIII, R¹ isselected from hydrogen, halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,hydroxyl, C₁₋₆ alkoxy, NH₂, NHC₁₋₆ alkyl, and N(C₁₋₆ alkyl)₂.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n), XII(o) or XIII, R¹ isselected from hydrogen, halogen, CN, CF₃ and methyl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n), XII(o) or XIII, R¹ ishydrogen.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R³ is selectedfrom hydrogen, halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)OR^(a),C(O)NR^(b)R^(c), OR^(a), NR^(b)R^(c), C₆₋₁₀ aryl and 5-10 memberedheteroaryl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R³ is selectedfrom hydrogen, halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, hydroxyl, C₁₋₆alkoxy, NH₂, NHC₁₋₆ alkyl, and N(C₁₋₆ alkyl)₂.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R³ is selectedfrom hydrogen, halogen, CN, CF₃ and methyl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R³ ishydrogen.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R¹ and R³ areeach hydrogen.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n), XII(o), or XIII, R⁴ isselected from hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)R^(a),C(O)OR^(a), C(O)NR^(b)R^(c) and SO₂R^(a).

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n) or XII(o), R⁴ ishydrogen.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a), V(b), VI, VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a),XI(b), XII(a), XII(b), XII(c), XII(d), XII(e), XII(f), XII(g), XII(h),XII(i), XII(j), XII(k), XII(l), XII(m), XII(n), XII(o), or XIII, R¹, R³and R⁴ are each hydrogen.

In some embodiments of compounds of Formula I, III, IV(b), V(b), VI,VII(b), VIII(b), IX, X(b), XI(b), XII(a), XII(c), XII(e), XII(f),XII(h), XII(j), XII(k), XII(m), XII(o) or XIII, R⁸ and R⁹, at eachoccurrence, are each independently selected from hydrogen, halogen andC₁₋₆ alkyl.

In some embodiments of compounds of Formula I, III, IV(b), V(b), VI,VII(b), VIII(b), IX, X(b), XI(b), XII(a), XII(c), XII(e), XII(f),XII(h), XII(j), XII(k), XII(m), XII(o) or XIII, R⁸ and R⁹, at eachoccurrence, are each hydrogen.

In some embodiments, the compound is selected from the compounds inTable 2, or a pharmaceutically acceptable salt thereof.

The compounds and compositions described and/or disclosed hereinmodulate the contractility of the skeletal sarcomere. Specifically, thecompounds modulate the troponin complex of the fast skeletal musclesarcomere through one or more of fast skeletal myosin, actin,tropomyosin, troponin C, troponin I, and troponin T, and fragments andisoforms thereof. As used in this context, “modulate” means eitherincreasing or decreasing activity. In some instances, the compoundsdescribed and/or disclosed herein potentiate (i.e., increase activity)of one or more of fast skeletal myosin, actin, tropomyosin, troponin C,troponin I, and troponin T, and fragments and isoforms thereof. In otherinstances, the compounds described and/or disclosed herein inhibit(i.e., decrease activity) of one or more of fast skeletal myosin, actin,tropomyosin, troponin C, troponin I, and troponin T, and fragments andisoforms thereof.

In both preclinical and clinical settings, activators of the fastskeletal troponin complex have been shown to amplify the response offast skeletal muscle to nerve stimulation, resulting in an increase inmuscle force development at sub-maximal muscle activation (see, e.g.,Russell et al., “The Fast Skeletal Troponin Activator, CK-2017357,Increases Skeletal Muscle Force in vitro and in situ”, 2009 ExperimentalBiology Conference, New Orleans, La., April 2009). Activators of thefast skeletal troponin complex have been shown to increase thesensitivity of skinned skeletal muscle fibers to calcium, and in livingmuscle to the frequency of stimulation, each of which results in anincrease in muscle force development at sub-maximal muscle activation.Such activators have also been shown to reduce muscle fatigue and/or toincrease the overall time to fatigue in normal and low oxygenatedconditions (see, e.g., Russell et al., “The Fast Skeletal TroponinActivator, CK-2017357, Increases Skeletal Muscle Force and ReducesMuscle Fatigue in vitro and in situ”, 5th Cachexia Conference,Barcelona, Spain, December 2009; Hinken et al., “The Fast SkeletalTroponin Activator, CK-2017357, Reduces Muscle Fatigue in an in situModel of Vascular Insufficiency”, Society for Vascular Medicine's 2010Annual Meeting: 21st Annual Scientific Sessions, Cleveland, Ohio, April2010). The increase in muscle force in response to nerve input has beendemonstrated in healthy human volunteers as well (see, e.g., Hansen etal., “CK-2017357, a Novel Activator of Fast Skeletal Muscle, IncreasesIsometric Force Evoked by Electrical Stimulation of the AnteriorTibialis Muscle in Healthy Male Subjects”, Society for Neuroscience 40thAnnual Meeting: Neuroscience 2010, November 2010). Work in additionalpreclinical models of muscle function suggests that activators of thefast skeletal troponin complex also cause an increase in muscle powerand/or endurance. These pharmacological properties suggest thismechanism of action could have application in conditions, for example,where neuromuscular function is impaired.

Provided are methods for enhancing fast skeletal muscle efficiency in apatient in need thereof, comprising administering to said patient aneffective amount of a compound or composition described and/or disclosedherein that selectively binds the troponin complex of fast skeletalmuscle fiber or sarcomere. In some embodiments, the compound disclosedand/or described herein activates fast skeletal muscle fibers orsarcomeres. In some embodiments, administration of a compound disclosedand/or described herein results in an increase in fast skeletal musclepower output. In some embodiments, administration of a compounddisclosed and/or described herein results in increased sensitivity offast skeletal muscle fibers or sarcomeres to calcium ion, as compared tofast skeletal muscle fibers or sarcomeres untreated with the compound.In some embodiments, administration of a compound disclosed and/ordescribed herein results in a lower concentration of calcium ionscausing fast skeletal muscle myosin to bind to actin. In someembodiments, administration of a compound disclosed and/or describedherein results in the fast skeletal muscle fiber generating force to agreater extent at submaximal levels of muscle activation.

Also provided is a method for sensitizing a fast skeletal muscle fiberto produce force in response to a lower concentration of calcium ion,comprising contacting the fast skeletal muscle fiber with a compound orcomposition described and/or disclosed herein that selectively binds totroponin complexes in the fast skeletal muscle sarcomere. In someembodiments, contacting the fast skeletal muscle fiber with the compoundresults in activation of the fast skeletal muscle fiber at a lowercalcium ion concentration than in an untreated fast skeletal musclefiber. In some embodiments, contacting the fast skeletal muscle fiberwith the compound results in the production of increased force at alower calcium ion concentration in comparison with an untreated fastskeletal muscle fiber.

Also provided is a method for increasing time to fast skeletal musclefatigue in a patient in need thereof, comprising contacting fastskeletal muscle fibers with a compound or composition described and/ordisclosed herein that selectively binds to the troponin complexes of thefast skeletal muscle fibers. In some embodiments, the compound binds toform ligand-troponin-calcium ion complexes that activate the fastskeletal muscle fibers. In some embodiments, formation of the complexesand/or activation of the fast skeletal muscle fibers results in enhancedforce and/or increased time to fatigue as compared to untreated fastskeletal muscle fibers contacted with a similar calcium ionconcentration.

The compounds and pharmaceutical compositions described and/or disclosedherein are capable of modulating the contractility of the fast skeletalsarcomere in vivo, and can have application in both human and animaldisease. Modulation would be desirable in a number of conditions ordiseases, including, but not limited to, 1) neuromuscular disorders,such as Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy(SMA), peripheral neuropathies and myasthenia gravis; 2) disorders ofvoluntary muscle, including muscular dystrophies, myopathies andconditions of muscle wasting, such as sarcopenia and cachexia syndromes(e.g., cachexia syndromes caused by diseases such as cancer, heartfailure, chronic obstructive pulmonary disease (COPD), and chronickidney disease/dialysis), and rehabilitation-related deficits, such asthose associated with recovery from surgery (e.g. post-surgical muscleweakness) prolonged bed rest or stroke rehabilitation; 3) centralnervous system (CNS) disorders in which muscle weakness, atrophy andfatigue are prominent symptoms, such as multiple sclerosis, Parkinson'sdisease, stroke and spinal cord injury; and 4) muscle symptoms stemmingfrom systemic disorders, including Peripheral Vascular Disease (PVD) orPeripheral Arterial Disease (PAD) (e.g., claudication), metabolicsyndrome, chronic fatigue syndrome, obesity and frailty due to aging.

The compounds and compositions described and/or disclosed herein may beused to treat neuromuscular diseases, i.e., diseases that affect anypart of the nerve-muscle unit. Neuromuscular diseases include, forexample: 1) diseases of the motor unit, including but not limited toAmyotrophic Lateral Sclerosis (ALS) including bulbar and primary lateralsclerosis (PLS) variants; spinal muscular atrophy types 1-4; Kennedysyndrome; post-polio syndrome; motor neuropathies including, forexample, critical illness polyneuropathy; multifocal motor neuropathywith conduction block; Charcot-Marie-Tooth disease and other hereditarymotor and sensory neuropathies; and Guillain-Barre Syndrome, 2)disorders of the neuromuscular junction, including myasthenia gravis,Lambert-Eaton myasthenic syndrome, and prolonged neuromuscular blockadedue to drugs or toxins; and 3) peripheral neuropathies, such as acuteinflammatory demyelinating polyradiculoneuropathy, diabetic neuropathy,chronic inflammatory demyelinating polyradiculoneuropathy, traumaticperipheral nerve lesions, neuropathy of leprosy, vasculitic neuropathy,dermatomyositis/polymyositis and neuropathy of Friedreich Ataxia.

The compounds and compositions described and/or disclosed herein may beused to treat disorders of voluntary muscle. Disorders of voluntarymuscle include 1) muscular dystrophies (including, for example,Duchenne, Becker, Limb-Girdle, Facioscapulohumeral, limb girdle,Emery-Dreyfus, oculopharyngeal and congenital muscular dystrophies); and2) myopathies, such as nemaline myopathy, central core disease,congenital myopathies, mitochondrial myopathies, acute myopathy;inflammatory myopathies (such as dermatomyositis/polymyositis andinclusion body myositis), endocrine myopathies (such as those associatedwith hyper- or hypothyroidism), Cushing's or Addison's syndrome ordisease and pituitary gland disorders, metabolic myopathies (such asglycogen storage diseases, e.g., McArdle's disease, Pompe disease, etc),drug-induced myopathy (statins, anti-retroviral drugs, steroid myopathy)restrictive lung disease, sarcoidosis, Schwartz-Jampel Syndrome, focalmuscular atrophies, and distal myopathies.

The compounds and compositions described and/or disclosed herein may beused to treat or Amyotrophic Lateral Sclerosis (ALS). ALS is a diseasethat generally arises later in life (Age 50+) and has a rapidprogression from initial limb weakness to paralysis and death. Commonlife expectancy after diagnosis is 3-5 years. The cause of disease formost ALS patients is unknown (termed the spontaneous form) while a smallproportion of patients have an inherited form (familial) of disease. Thecondition causes progressive death of motor neurons through causes thatare not clear. Surviving motor units attempt to compensate for dyingones by innervating more fibers (termed sprouting) but this can onlypartially correct muscle function, as muscles are subsequently moreprone to problems of coordination and fatigue. Eventually, survivingmotor neurons die, resulting in complete paralysis of the affectedmuscle. The disease is commonly fatal through the eventual loss ofinnervation to the diaphragm, resulting in respiratory failure. Currenttreatment options for ALS are limited.

The compounds and compositions described and/or disclosed herein may beused to treat Spinal Muscular Atrophy (SMA). SMA is a genetic disorderthat arises through the mutation of a protein, SMN1, that appears to berequired for the survival and health of motor neurons. The disease ismost common in children as the majority of patients only survive until11-12 years of age. There is currently no available treatment for SMA.

The compounds and compositions described and/or disclosed herein may beused to treat myasthenia gravis. Myasthenia gravis is a chronicautoimmune neuromuscular disease wherein the body produces antibodiesthat block, alter, or destroy proteins involved in signaling at theneuromuscular junction, thus preventing muscle contraction fromoccurring. These proteins include nicotinic acetylcholine receptor(AChR) or, less frequently, a muscle-specific tyrosine kinase (MuSK)involved in AChR clustering (see, e.g., Drachman, N. Eng. J. of Med.,330:1797-1810, 1994). The disease is characterized by varying degrees ofweakness of the skeletal (voluntary) muscles of the body. The hallmarkof myasthenia gravis is muscle weakness that increases during periods ofactivity and improves after periods of rest. Although myasthenia gravismay affect any voluntary muscle, certain muscles, such as those thatcontrol eye and eyelid movement, facial expression, chewing, talking,and swallowing are often, but not always, involved in the disorder. Themuscles that control breathing and neck and limb movements may also beaffected. In most cases, the first noticeable symptom is weakness of theeye muscles. In others, difficulty in swallowing and slurred speech maybe the first signs. The degree of muscle weakness involved in myastheniagravis varies greatly among patients, ranging from a localized form,limited to eye muscles (ocular myasthenia), to a severe or generalizedform in which many muscles—sometimes including those that controlbreathing—are affected. Symptoms, which vary in type and severity, mayinclude a drooping of one or both eyelids (ptosis), blurred or doublevision (diplopia) due to weakness of the muscles that control eyemovements, unstable or waddling gait, weakness in arms, hands, fingers,legs, and neck, a change in facial expression, difficulty in swallowingand shortness of breath, and impaired speech (dysarthria). Generalizedweakness develops in approximately 85% of patients.

The compounds and compositions described and/or disclosed herein may beused to treat sarcopenia, e.g., sarcopenia associated with aging ordisease (e.g. HIV infection). Sarcopenia is characterized by a loss ofskeletal muscle mass, quality, and strength. Clinically, a decline inskeletal muscle tissue mass (muscle atrophy) contributes to frailty inolder individuals. In human males, muscle mass declines by one-thirdbetween the ages of 50 and 80. In older adults, extended hospitalizationcan result in further disuse atrophy leading to a potential loss of theability for independent living and to a cascade of physical decline.Moreover, the physical aging process profoundly affects bodycomposition, including significant reductions in lean body mass andincreases in central adiposity. The changes in overall adiposity and fatdistribution appear to be important factors in many common age-relateddiseases such as hypertension, glucose intolerance and diabetes,dyslipidemia, and atherosclerotic cardiovascular disease. In addition,it is possible that the age-associated decrement in muscle mass, andsubsequently in strength and endurance, may be a critical determinantfor functional loss, dependence and disability. Muscle weakness is alsoa major factor prediposing the elderly to falls and the resultingmorbidity and mortality.

The compounds and compositions described and/or disclosed herein may beused to treat cachexia. Cachexia is a state often associated with canceror other serious diseases or conditions, (e.g, chronic obstructivepulmonary disease, heart failure, chronic kidney disease, kidneydialysis), that is characterized by progressive weight loss, muscleatrophy and fatigue, due to the deletion of adipose tissue and skeletalmuscle.

The compounds and compositions described and/or disclosed herein may beused to treat muscular dystrophies. Muscular dystrophy can becharacterized by progressive muscle weakness, destruction andregeneration of the muscle fibers, and eventual replacement of themuscle fibers by fibrous and fatty connective tissue.

The compounds and compositions described and/or disclosed herein may beused to treat post-surgical muscle weakness, which is a reduction in thestrength of one or more muscles following surgical procedure. Weaknessmay be generalized (i.e. total body weakness) or localized to a specificarea, side of the body, limb, or muscle.

The compounds and compositions described and/or disclosed herein may beused to treat post-traumatic muscle weakness, which is a reduction inthe strength of one or more muscles following a traumatic episode (e.g.bodily injury). Weakness may be generalized (i.e. total body weakness)or localized to a specific area, side of the body, limb, or muscle.

The compounds and compositions described and/or disclosed herein may beused to treat muscle weakness and fatigue produced by peripheralvascular disease (PVD) or peripheral artery disease (PAD). Peripheralvascular disease is a disease or disorder of the circulatory systemoutside of the brain and heart. Peripheral artery disease (PAD), alsoknown as peripheral artery occlusive disease (PAOD), is a form of PVD inwhich there is partial or total blockage of an artery, usually oneleading to a leg or arm. PVD and/or PAD can result from, for example,atherosclerosis, inflammatory processes leading to stenosis,embolus/thrombus formation, or damage to blood vessels due to disease(e.g., diabetes), infection or injury. PVD and/or PAD can cause eitheracute or chronic ischemia, typically of the legs. The symptoms of PVDand/or PAD include pain, weakness, numbness, or cramping in muscles dueto decreased blood flow (claudication), muscle pain, ache, cramp,numbness or fatigue that occurs during exercise and is relieved by ashort period of rest (intermittent claudication), pain while resting(rest pain) and biological tissue loss (gangrene). The symptoms of PVDand/or PAD often occur in calf muscles, but symptoms may also beobserved in other muscles such as the thigh or hip. Risk factors for PVDand/or PAD include age, obesity, sedentary lifestyle, smoking, diabetes,high blood pressure, and high cholesterol (i.e., high LDL, and/or hightriglycerides and/or low HDL). People who have coronary heart disease ora history of heart attack or stroke generally also have an increasedfrequency of having PVD and/or PAD. Activators of the fast skeletaltroponin complex have been shown to reduce muscle fatigue and/or toincrease the overall time to fatigue in in vitro and in situ models ofvascular insufficiency (see, e.g., Russell et al., “The Fast SkeletalTroponin Activator, CK-2017357, Increases Skeletal Muscle Force andReduces Muscle Fatigue in vitro and in situ”, 5th Cachexia Conference,Barcelona, Spain, December 2009; Hinken et al., “The Fast SkeletalTroponin Activator, CK-2017357, Reduces Muscle Fatigue in an in situModel of Vascular Insufficiency”, Society for Vascular Medicine's 2010Annual Meeting: 21st Annual Scientific Sessions, Cleveland, Ohio, April2010).

The compounds and compositions described and/or disclosed herein may beused to treat symptoms of frailty, e.g., frailty associated with aging.Frailty is characterized by one or more of unintentional weight loss,muscle weakness, slow walking speed, exhaustion, and low physicalactivity.

The compounds and compositions described and/or disclosed herein may beused to treat muscle weakness and/or fatigue due to wasting syndrome,which is a condition characterized by involuntary weight loss associatedwith chronic fever and diarrhea. In some instances, patients withwasting syndrome lose 10% of baseline body weight within one month.

The compounds and compositions described and/or disclosed herein may beused to treat muscular diseases and conditions caused by structuraland/or functional abnormalities of skeletal muscle tissue, includingmuscular dystrophies, congenital muscular dystrophies, congenitalmyopathies, distal myopathies, other myopathies (e.g., myofibrillar,inclusion body), myotonic syndromes, ion channel muscle diseases,malignant hyperthermias, metabolic myopathies, congenital myasthenicsyndromes, sarcopenia, muscle atrophy and cachexia.

The compounds and compositions described and/or disclosed herein alsomay be used to treat diseases and conditions caused by muscledysfunction originating from neuronal dysfunction or transmission,including amyotrophic lateral sclerosis, spinal muscular atrophies,hereditary ataxias, hereditary motor and sensory neuropathies,hereditary paraplegias, stroke, multiple sclerosis, brain injuries withmotor deficits, spinal cord injuries, Alzheimer's disease, Parkinson'sdisease with motor deficits, myasthenia gravis and Lambert-Eatonsyndrome.

The compounds and compositions described and/or disclosed herein alsomay be used to treat diseases and conditions caused by CNS, spinal cordor muscle dysfunction originating from endocrine and/or metabolicdysregulation, including claudication secondary to peripheral arterydisease, hypothyroidism, hyper- or hypo-parathyroidism, diabetes,adrenal dysfunction, pituitary dysfunction and acid/base imbalances.

The compounds and compositions described and/or disclosed herein may beadministered alone or in combination with other therapies and/ortherapeutic agents useful in the treatment of the aforementioneddisorders.

The compounds and compositions described and/or disclosed herein may becombined with one or more other therapies to treat ALS. Examples ofsuitable therapies include riluzole, baclofen, diazepam, trihexyphenidyland amitriptyline. In some embodiments, the compounds and compositionsdescribed and/or disclosed herein are combined with riluzole to treat asubject suffering from ALS.

The compounds and compositions described and/or disclosed herein may becombined with one or more other therapies to treat myasthenia gravis.Examples of suitable therapies include administration ofanticholinesterase agents (e.g., neostigmine, pyridostigmine), whichhelp improve neuromuscular transmission and increase muscle strength;administration of immunosuppressive drugs (e.g., prednisone,cyclosporine, azathioprine, mycophenolate mofetil) which improve musclestrength by suppressing the production of abnormal antibodies;thymectomy (i.e., the surgical removal of the thymus gland, which oftenis abnormal in myasthenia gravis patients); plasmapheresis; andintravenous immune globulin.

The compounds and compositions described and/or disclosed herein may becombined with one or more other therapies to treat PVD or PAD (e.g.,claudication). Treatment of PVD and PAD is generally directed toincreasing arterial blood flow, such as by smoking cessation,controlling blood pressure, controlling diabetes, and exercising.Treatment can also include medication, such as medicines to help improvewalking distance (e.g., cilostazol, pentoxifylline), antiplatelet agents(e.g., aspirin, ticlopidine, clopidogrel), anticoagulents (e.g.,heparin, low molecular weight heparin, warfarin, enoxaparin)throbmolytics, antihypertensive agents (e.g., diuretics, ACE inhibitors,calcium channel blockers, beta blockers, angiotensin II receptorantagonists), and cholesterol-lowering agents (e.g., statins). In somepatients, angioplasty, stenting, or surgery (e.g., bypass surgery orsurgery to remove an atherosclerotic plaque) may be necessary.

Suitable therapeutic agents include, for example, anti-obesity agents,anti-sarcopenia agents, anti-wasting syndrome agents, anti-frailtyagents, anti-cachexia agents, anti-muscle spasm agents, agents againstpost-surgical and post-traumatic muscle weakness, and anti-neuromusculardisease agents.

Suitable additional therapeutic agents include, for example: orlistat,sibramine, diethylpropion, phentermine, benzaphetamine, phendimetrazine,estrogen, estradiol, levonorgestrel, norethindrone acetate, estradiolvalerate, ethinyl estradiol, norgestimate, conjugated estrogens,esterified estrogens, medroxyprogesterone acetate, testosterone,insulin-derived growth factor, human growth hormone, riluzole,cannabidiol, prednisone, albuterol, non-steroidal anti-inflammatorydrugs, and botulinum toxin.

Other suitable therapeutic agents include TRH, diethylstilbesterol,theophylline, enkephalins, E series prostaglandins, compounds disclosedin U.S. Pat. No. 3,239,345 (e.g., zeranol), compounds disclosed in U.S.Pat. No. 4,036,979 (e.g., sulbenox), peptides disclosed in U.S. Pat. No.4,411,890, growth hormone secretagogues such as GHRP-6, GHRP-1(disclosed in U.S. Pat. No. 4,411,890 and publications WO 89/07110 andWO 89/07111), GHRP-2 (disclosed in WO 93/04081), NN703 (Novo Nordisk),LY444711 (Lilly), MK-677 (Merck), CP424391 (Pfizer) and B-HT920, growthhormone releasing factor and its analogs, growth hormone and its analogsand somatomedins including IGF-1 and IGF-2, alpha-adrenergic agonists,such as clonidine or serotonin 5-HT_(D) agonists, such as sumatriptan,agents which inhibit somatostatin or its release, such as physostigmine,pyridostigmine, parathyroid hormone, PTH(1-34), and bisphosphonates,such as MK-217 (alendronate).

Still other suitable therapeutic agents include estrogen, testosterone,selective estrogen receptor modulators, such as tamoxifen or raloxifene,other androgen receptor modulators, such as those disclosed in Edwards,J. P. et. al., Bio. Med. Chem. Let., 9, 1003-1008 (1999) and Hamann, L.G. et. al., J. Med. Chem., 42, 210-212 (1999), and progesterone receptoragonists (“PRA”), such as levonorgestrel, medroxyprogesterone acetate(MPA).

Other suitable therapeutic agents include anabolic agents, such asselective androgen receptor modulators (SARMs); antagonists of theactivin receptor pathway, such as anti-myostatin antibodies or solubleactivin receptor decoys, including ACE-031 (Acceleron Pharmaceuticals, asoluble activin receptor type IIB antagonist), MYO-027/PFE-3446879(Wyeth/Pfizer, an antibody myostatin inhibitor), AMG-745 (Amgen, apeptibody myostatin inhibitor), and an ActRIIB decoy receptor (see Zhouet al., Cell, 142, 531-543, Aug. 20, 2010); and anabolic steroids.

Still other suitable therapeutic agents include aP2 inhibitors, such asthose disclosed in U.S. Pat. No. 6,548,529, PPAR gamma antagonists, PPARdelta agonists, beta 3 adrenergic agonists, such as AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer), other beta 3agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134,5,776,983 and 5,488,064, a lipase inhibitor, such as orlistat or ATL-962(Alizyme), a serotonin (and dopamine) reuptake inhibitor, such assibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), athyroid receptor beta drug, such as a thyroid receptor ligand asdisclosed in WO 97/21993, WO 99/00353, and GB98/284425, and anorecticagents, such as dexamphetamine, phentermine, phenylpropanolamine ormazindol.

Still other suitable therapeutic agents include HIV and AIDS therapies,such as indinavir sulfate, saquinavir, saquinavir mesylate, ritonavir,lamivudine, zidovudine, lamivudine/zidovudine combinations, zalcitabine,didanosine, stavudine, and megestrol acetate.

Still other suitable therapeutic agents include antiresorptive agents,hormone replacement therapies, vitamin D analogues, elemental calciumand calcium supplements, cathepsin K inhibitors, MMP inhibitors,vitronectin receptor antagonists, Src SH.sub.2 antagonists, vacuolarH⁺-ATPase inhibitors, ipriflavone, fluoride, Tibo lone, pro stanoids,17-beta hydroxysteroid dehydrogenase inhibitors and Src kinaseinhibitors.

The above therapeutic agents, when employed in combination with thecompounds and compositions disclosed and/or described herein, may beused, for example, in those amounts indicated in the Physicians' DeskReference (PDR) or as otherwise determined by one of ordinary skill inthe art.

The compounds and compositions disclosed and/or described herein areadministered at a therapeutically effective dosage, e.g., a dosagesufficient to provide treatment for the disease state. While humandosage levels have yet to be optimized for the chemical entitiesdescribed herein, generally, a daily dose ranges from about 0.05 to 100mg/kg of body weight; in some embodiments, from about 0.10 to 10.0 mg/kgof body weight, and in some embodiments, from about 0.15 to 1.0 mg/kg ofbody weight. Thus, for administration to a 70 kg person, in someembodiments, the dosage range would be about from 3.5 to 7000 mg perday; in some embodiments, about from 7.0 to 700.0 mg per day, and insome embodiments, about from 10.0 to 100.0 mg per day. The amount of thechemical entity administered will be dependent, for example, on thesubject and disease state being treated, the severity of the affliction,the manner and schedule of administration and the judgment of theprescribing physician. For example, an exemplary dosage range for oraladministration is from about 70 mg to about 700 mg per day, and anexemplary intravenous administration dosage is from about 70 mg to about700 mg per day, each depending upon the compound pharmacokinetics.

Administration of the compounds and compositions disclosed and/ordescribed herein can be via any accepted mode of administration fortherapeutic agents including, but not limited to, oral, sublingual,subcutaneous, parenteral, intravenous, intranasal, topical, transdermal,intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, orintraocular administration. In some embodiments, the compound orcomposition is administered orally or intravenously. In someembodiments, the compound or composition disclosed and/or describedherein is administered orally.

Pharmaceutically acceptable compositions include solid, semi-solid,liquid and aerosol dosage forms, such as tablet, capsule, powder,liquid, suspension, suppository, and aerosol forms. The compoundsdisclosed and/or described herein can also be administered in sustainedor controlled release dosage forms (e.g., controlled/sustained releasepill, depot injection, osmotic pump, or transdermal (includingelectrotransport) patch forms) for prolonged timed, and/or pulsedadministration at a predetermined rate. In some embodiments, thecompositions are provided in unit dosage forms suitable for singleadministration of a precise dose.

The compounds disclosed and/or described herein can be administeredeither alone or in combination with one or more conventionalpharmaceutical carriers or excipients (e.g., mannitol, lactose, starch,magnesium stearate, sodium saccharine, talcum, cellulose, sodiumcrosscarmellose, glucose, gelatin, sucrose, magnesium carbonate). Ifdesired, the pharmaceutical composition can also contain minor amountsof nontoxic auxiliary substances such as wetting agents, emulsifyingagents, solubilizing agents, pH buffering agents and the like (e.g.,sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitanmonolaurate, triethanolamine acetate, triethanolamine oleate).Generally, depending on the intended mode of administration, thepharmaceutical composition will contain about 0.005% to 95%, or about0.5% to 50%, by weight of a compound disclosed and/or described herein.Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa.

In some embodiments, the compositions will take the form of a pill ortablet and thus the composition may contain, along with a compoundsdisclosed and/or described herein, one or more of a diluent (e.g.,lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesiumstearate), and/or a binder (e.g., starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Othersolid dosage forms include a powder, marume, solution or suspension(e.g., in propylene carbonate, vegetable oils or triglycerides)encapsulated in a gelatin capsule.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing or suspending etc. a compounddisclosed and/or described herein and optional pharmaceutical additivesin a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols,ethanol or the like) to form a solution or suspension. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, as emulsions, or in solid forms suitable for dissolution orsuspension in liquid prior to injection. The percentage of the compoundcontained in such parenteral compositions depends, for example, on thephysical nature of the compound, the activity of the compound and theneeds of the subject. However, percentages of active ingredient of 0.01%to 10% in solution are employable, and may be higher if the compositionis a solid which will be subsequently diluted to another concentration.In some embodiments, the composition will comprise from about 0.2 to 2%of a compound disclosed and/or described herein in solution.

Pharmaceutical compositions of the compounds disclosed and/or describedherein may also be administered to the respiratory tract as an aerosolor solution for a nebulizer, or as a microfine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase, the particles of the pharmaceutical composition may have diametersof less than 50 microns, or in some embodiments, less than 10 microns.

In addition, pharmaceutical compositions can include a compounddisclosed and/or described herein and one or more additional medicinalagents, pharmaceutical agents, adjuvants, and the like. Suitablemedicinal and pharmaceutical agents include those described herein.

The following examples serve to more fully describe the inventiondescribed herein. It is understood that these examples in no way serveto limit the true scope of this invention, but rather are presented forillustrative purposes.

EXAMPLE 1 Preparation ofN-(5-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1H-indazol-3-yl)acetamide

6-Chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine

A solution of (2-(4-fluorophenyl)-2-methylpropan-1-amine (27 g, 160mmol, 1.6 equiv), 3,6-dichloropyridazine (15 g, 100 mmol, 1.0 equiv) andK₂CO₃ (42 g, 302 mmol, 3.0 equiv) in isopropanol (15 mL) was stirred at100° C. for 36 hours. The cooled mixture was partitioned between waterand EtOAc and the organic fraction was dried over Na₂SO₄ andconcentrated in vacuo. Partial purification over silica gel using a30-75% gradient of EtOAc/hexanes gave the desired product (29.6 g, 103%)which was used without further purification.

2-Fluoro-5-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)benzonitrile

To a solution of6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine (5.0 g,23 mmol, 1.0 equiv) and K₂CO₃ (9.4 g, 68 mmol, 3.0 equiv) in dioxane (35mL) was added Pd(dppf)Cl₂ (1.7 g, 2.3 mmol, 0.1 equiv) and3-cyano-4-fluorophenylboronic acid (5.0 g, 30 mmol, 1.3 equiv). Themixture was stirred at 80° C. for 3 hours after which it was allowed tocool to room temperature and concentrated in vacuo. The residue wasdiluted with EtOAc, washed with saturated NaHCO₃, dried over Na₂SO₄ andevaporated to dryness. The residue was purified by reverse phase HPLCusing a CH₃CN/water gradient to give the desired product (5.3 g, 63%).

5-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1H-indazol-3-amine

To a solution of2-fluoro-5-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)benzonitrile(0.53 g, 1.5 mmol, 1.0 equiv) in n-butanol (10 mL) was added hydrazinemonohydrate (1.0 mL, 32 mmol, 20 equiv). The mixture was stirred at 110°C. for two hours followed by evaporation of the solvents in vacuo.Purification on a preparatory TLC plate using 5% MeOH/DCM as eluent gavethe desired product (195 mg, 36%), m/z=377.1 [M+H].

N-(5-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1H-indazol-3-yl)acetamide

To a solution of5-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1H-indazol-3-amine(50 mg, 133 μmol) in pyridine (1 mL) was added acetyl chloride (9.5 μL,133 μmol). The mixture was stirred for 15 min, concentrated, purified byreverse phase chromatography using a CH₃CN/water gradient to afford 25mg of white solid, m/z=419.9 [M+H].

EXAMPLE 2 Preparation ofN-(2-(4-Fluorophenyl)-2-methylpropyl)-6-(1H-pyrazol-1-yl)pyridazin-3-amine

Step 1

To a solution of pyrazole (3.69 g, 25 mmol, 1.0 equiv) in NMP (25 mL)was added sodium hydride (60% dispersion in mineral oil, 1.5 g, 38 mmol,1.5 equiv). The mixture was stirred for 15 min, followed by the additionof 3,6-dichloropyridazine (3.02 g, 25 mmol, 1.0 equiv). The reactionmixture was stirred for 1.5 h and then diluted with water (50 mL) andethyl acetate (100 mL). After transferring to a separatory funnel andshaking, the organic layer was separated from the aqueous layer and thenwashed with brine (3×50 mL). The organic layer was then dried overNa₂SO₄, filtered, and concentrated to give 3.89 g of3-chloro-6-(1H-pyrazol-1-yl)pyridazine as a crude tan solid that wasused directly in the next step.

Step 2

To a 5 mL microwave vial was added3-chloro-6-(1H-pyrazol-1-yl)pyridazine (320 mg, 1.8 mmol, 1.0 equiv),2-(4-fluorophenyl)-2-methylpropan-1-amine (386 mg, 2.3 mmol, 1.3 equiv),diisopropylethylamine (620 μL, 3.6 mmol, 2.0 equiv), and NMP (4 mL). Thereaction was heated in a microwave reactor to 250° C. and stirred for 15min. A portion (roughly a third) of the reaction was purified by reversephase chromatography and then silica gel chromatography (10% MeOH/DCM)to give 61 mg ofN-(2-(4-fluorophenyl)-2-methylpropyl)-6-(1H-pyrazol-1-yl)pyridazin-3-amine,m/z=312.1 [M+H].

EXAMPLE 3 Preparation of 5-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1,3,4-oxadiazol-2(3H)-one

Methyl6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-3-carboxylate

To a 25 mL round bottom flask was added methyl6-chloropyridazine-3-carboxylate (0.50 g, 2.90 mmol, 1.0 equiv),2-(4-fluorophenyl)-2-methylpropan-1-amine (0.60 g, 3.6 mmol, 1.2 equiv),potassium carbonate (300 mg, 2.2 mmol, 0.75 equiv), and isopropanol (3mL). The reaction mixture was stirred and heated at 120° C. for 12 h.The reaction was then filtered through celite, concentrated, andpurified by silica gel chromatography (0-40% EtOAC/hexanes) to afford360 mg (43%) of methyl6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-3-carboxylate as anoff-white foam.

5-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1,3,4-oxadiazol-2(3H)-one

To a 25 mL round bottom flask was added methyl6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-3-carboxylate (100mg, 0.3 mmol, 1.0 equiv), hydrazine hydrate (1 mL), and ethanol (5 mL)).The reaction was refluxed for 2 h and concentrated.N,N′-Carbonyldiimidazole (100 mg, 0.6 mmol, 2.0 equiv) and DMF (1 mL)were then added to the crude product and the reaction was heated to 90°C. for 1.5 h. The reaction mixture was directly purified by reversephase column chromatography to afford 72 mg (67%) of5-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1,3,4-oxadiazol-2(3H)-oneas a white solid, m/z=330.0 [M+H].

EXAMPLE 4 Preparation of6-(2-Amino-1H-imidazol-4-yl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine

2-Bromo-1-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)ethanone

6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine (300 mg,1.1 mmol, 1.0 equiv) and dioxane (5 mL) were added to a microwave vialand sonication was applied until the mixture was homogeneous.Tributyl(1-ethoxyvinyl)stannane (475 μL, 1.4 mmol, 1.3 equiv) andtrans-dichlorobis(triphenylphosphine)palladium (30 mg, 0.04 mmol, 0.03equiv) were then added, and the reaction was heated in a microwavereactor at 150° C. for 20 min. The reaction was concentrated, dissolvedin EtOAc (25 mL), and mixed with 2.0 M potassium fluoride (5 mL). Themixture was filtered through celite, and then washed with water, driedover Na₂SO₄, filtered, and concentrated. The crude solid was redissolvedin 50% THF/water (4 mL), followed by the addition of NBS (300 mg, 1.7mmol, 1.5 equiv). The reaction mixture was stirred for 1 h and thendiluted with brine (20 mL) and ethyl acetate (20 mL). After transferringto a separatory funnel and shaking, the organic layer was separated fromthe aqueous layer. The organic layer was then dried over Na₂SO₄,filtered, and concentrated to give a brown oil that was purified bysilica gel chromatography (0-100% EtOAC/hexanes) to afford 270 mg of2-bromo-1-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)ethanoneas an orange oil.

N-(4-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1H-imidazol-2-yl)acetamide

To a 3 mL microwave reaction vial was added2-bromo-1-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)ethanone(125 mg, 0.3 mmol, 1.0 equiv), acetyl guanidine (90 mg, 0.6 mmol, 2.0equiv) and acetonitrile (2 mL). The reaction was heated in a microwavereactor at 100° C. for 13 min. The reaction was filtered and directlypurified by reverse phase column chromatography to affordN-(4-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1H-imidazol-2-yl)acetamide(70 mg) as an white solid. m/z=369.2 [M+H]+.

6-(2-Amino-1H-imidazol-4-yl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine

To a 10 mL round bottom flask was addedN-(4-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1H-imidazol-2-yl)acetamide(22 mg, 59 μmol), concentrated HCl (100 μL) and methanol (1 mL). Thereaction was refluxed for 12 h and then concentrated, redissolved inEtOAc (10 mL), washed with saturated sodium carbonate (2×10 mL) andbrine (1×10 mL), dried (Na₂SO₄) and concentrated to yield 8 mg (42%) of6-(2-amino-1H-imidazol-4-yl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amineas a pale yellow solid, m/z=327.2 [M+H].

EXAMPLE 5 Preparation of6-(5-Amino-1H-pyrazol-3-yl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine

To a 20 dram vial was added2-bromo-1-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)ethanone(13 mg, 35 μmol, 1.0 equiv), sodium cyanide (25 mg, 500 μmol, 15.0equiv) and ethanol (1 mL). The reaction mixture was heated to 60° C. for30 min. After cooling to room temperature, the reaction was filtered.Hydrazine hydrate (250 μL) was then added, and the reaction mixture washeated to 100° C. for 2 h. The reaction was filtered and directlypurified by reverse phase column chromatography to afford6-(5-amino-1H-pyrazol-3-yl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine(2 mg) as an white solid, m/z=327.2 [M+H].

EXAMPLE 6 Preparation of6-Ethyl-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine

Step 1

To a 5 mL microwave reaction vial was added6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine (123 mg,441 μmol, 1.0 equiv), 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (159mg, 661 μmol, 1.5 equiv), Cl₂Pd(dppf) (54 mg, 66 μmol, 0.15 equiv),potassium carbonate (182 mg, 1.32 mmol, 3 equiv), and dioxane (21 mL).The reaction was heated in a microwave reactor at 140° C. for 12 min andthen diluted with water (20 mL) and ethyl acetate (50 mL). Aftertransferring to a separatory funnel and shaking, the organic layer wasseparated from the aqueous layer and then washed with brine (1×20 mL).The organic layer was then dried over Na₂SO₄, filtered, and concentratedto give a crude solid that was purified by silica gel columnchromatography (20-50% EtOAc/hexanes) to give 50 mg (46%) ofN-(2-(4-fluorophenyl)-2-methylpropyl)-6-vinylpyridazin-3-amine as awhite solid.

Step 2

The isolated product from Step 1 was dissolved in ethanol (10 mL) andtransferred to a 20 dram vial. Palladium (10% on carbon, 10 mg) was thenadded, and the reaction was stirred under 60 psi of hydrogen for 3 days.The reaction was then filtered, concentrated, and purified by reversephase column chromatography to afford 3 mg (10%) of6-ethyl-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine as aclear oil, m/z=274 [M+H].

EXAMPLE 7 Preparation of2-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)propan-2-ol

Methyl6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3-carboxylate

To a 20 dram vial was added methyl 6-chloropyridazine-3-carboxylate (510mg, 2.7 mmol, 1.0 equiv),(1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (738 mg, 4 mmol, 1.5equiv), DIPEA (0.7 mL, 4 mmol, 1.5 equiv), and NMP (2 mL). The reactionwas heated at 120° C. for 40 min and then diluted with water (20 mL) andethyl acetate (50 mL). After transferring to a separatory funnel andshaking, the organic layer was separated from the aqueous layer and thenwashed with brine (1×20 mL). The organic layer was then dried overNa₂SO₄, filtered, and concentrated to give a crude solid that waspurified by silica gel column chromatography (20-100% EtOAc/hexanes) togive 440 mg (48%) of methyl6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3-carboxylateas a white solid. m/z=331.1 [M+H]+.

2-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)propan-2-ol

A portion of the isolated methyl6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3-carboxylate(99 mg, 0.3 mmol, 1.0 equiv) was dissolved in THF (10 mL) andtransferred to a 20 dram vial. The mixture was cooled to 0° C. andMeMgBr (3M in Et₂O, 0.5 mL, 1.5 mmol, 5 equiv) was added. The reactionwas allowed to warm to rt and then stirred for 15 min. The reactionmixture was poured into a mixture of EtOAc (30 mL) and saturatedammonium chloride (15 mL). The organic layer was separated, dried overNa₂SO₄, filtered, and concentrated to give a crude solid that waspurified by silica gel column chromatography (0-20% MeOH/CH₂Cl₂) to give42 mg (43%) of2-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)propan-2-olas a white powder. m/z=317 [M+H]+

EXAMPLE 8 Preparation of1-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)ethanone

6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3-carbonitrile

To a 20 dram vial was added 6-chloropyridazine-3-carbonitrile (1.0 g,7.2 mmol, 1.0 equiv), (1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine(1.36 g, 7.6 mmol, 1.05 equiv), triethylamine (2.1 mL, 14.4 mmol, 2.0equiv), and NMP (2 mL). The reaction was heated at 130° C. for 12 h andthen diluted with water (20 mL) and ethyl acetate (50 mL). Aftertransferring to a separatory funnel and shaking, the organic layer wasseparated from the aqueous layer and then washed with brine (1×20 mL).The organic layer was then dried over Na₂SO₄, filtered, and concentratedto give a crude solid that was purified by silica gel columnchromatography (20-30% EtOAc/hexanes) to give 507 mg (25%) of6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3-carbonitrile.m/z=284 [M+H]+.

1-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)ethanone

6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3-carbonitrile(500 mg, 1.8 mmol, 1.0 equiv) was dissolved in THF (4.5 mL) andtransferred to a 20 dram vial. The mixture was cooled to 0° C. andMeMgBr (1.8 mL, 5.3 mmol of a 3M solution in Et₂O, 2.9 equiv) was added.The reaction was stirred at this temperature for 15 min. The reactionmixture was poured into ice water, acidified to pH of 2 with 2N aqueoushydrochloric acid, and then extracted EtOAc (30 mL). The organic layerwas then separated, dried over Na₂SO₄, filtered, and concentrated togive a crude solid that was purified by silica gel column chromatography(50% EtOAc/hexanes) to give 104 mg (18%) of1-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)ethanoneas a white powder. m/z=301.1 [M+H]+.

EXAMPLE 9 Preparation ofN-(2-(4-fluorophenyl)-2-methylpropyl)-6-(pyridin-2-yl)pyridazin-3-amine

To a 25 mL round bottom flask was added 2-bromopyridine (500 mg, 3.2mmol, 1.0 equiv), triisopropylborate (654 mg, 3.5 mmol, 1.1 equiv), andan 80% toluene/THF mixture (16 mL). The mixture was cooled to −78° C.After stirring for 10 min, n-BuLi (1.7 mL, 3.48 mmol, 1.1 equiv of a 2.0M/hexanes solution) was slowly added over an hour. After the additionwas complete, the reaction mixture was stirred for 30 min and allowed towarm to rt and stirred overnight. The reaction was then concentrated at100° C. and dried in vacuo for 2 h. To 100 mg of this crude solid in amicrowave vial was added6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine (70 mg,0.25 mmol), Pd₂ dba₃ (10 mg, 0.011 mmol), PO(tBu)₃ (5 mg, 0.030 mmol),potassium fluoride (43 mg, 0.75 mmol), and dioxane (0.75 mL). Thereaction was degassed with nitrogen for 5 minutes and then heated in amicrowave reactor at 160° C. for 15 min. The reaction was thenconcentrated, dissolved in EtOAc (25 mL), washed with water, dried overNa₂SO₄, filtered, concentrated, and purified by reverse phase columnchromatography to give 5 mg ofN-(2-(4-fluorophenyl)-2-methylpropyl)-6-(pyridin-2-yl)pyridazin-3-amineas a white solid. m/z=323.1 [M+H]+.

EXAMPLE 10 Preparation of6-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)nicotinamide

To a 20 dram vial was added 2-bromo-5-cyanopyridine (182 mg, 1.0 mmol,1.0 equiv), hexamethylditin (639 mg, 1.1 mmol, 1.1 equiv), Cl₂Pd(Ph₃P)₂(91 mg, 0.13 mmol, 0.13 equiv), triphenylarsine (34 mg, 0.11 mmol, 0.11equiv), and dioxane (7 mL). The reaction mixture was stirred and heatedto 80° C. for 12 h. The reaction was then concentrated, followed by theaddition of tert-butyl6-bromopyridazin-3-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate (423mg, 1.0 mmol, 1.0 equiv), Pd(Ph₃P)₄ (172 mg, 0.15 mmol, 0.15 equiv), andDMF (3.3 mL). The reaction was stirred and heated to 100° C. for 3 h.After cooling to room temperature, the reaction was diluted with aqueouspotassium fluoride (5 mL), extracted with ethyl acetate (20 mL) andwashed with brine (20 mL). The organic layer was then dried (Na₂SO₄),filtered, and concentrated to give crude tert-butyl6-(5-cyanopyridin-2-yl)pyridazin-3-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate.

To a 20 dram vial was added crude tert-butyl6-(5-cyanopyridin-2-yl)pyridazin-3-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate,hydrogen peroxide (2 mL), and potassium carbonate (150 mg). The reactionwas stirred for 30 min and then diluted with water (20 mL) and ethylacetate (50 mL). After transferring to a separatory funnel and shaking,the organic layer was separated from the aqueous layer and then washedwith brine (20 mL). The organic layer was then dried over Na₂SO₄,filtered, and concentrated to give a crude solid that was subsequentlytreated with 4N HCl/dioxane (1 mL). The reaction was stirred for 1 h atroom temperature, concentrated, quenched with aqueous sodiumbicarbonate, and extracted with ethyl acetate (20 mL). The organic layerwas then dried (Na₂SO₄), filtered, and concentrated to give a crudesolid that was purified by reverse phase column chromatography to afford10 mg of6-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)nicotinamide,m/z=366.1 [M+H].

EXAMPLE 11 Preparation of6-(2-aminopyridin-3-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine

N-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methyl)-6-(2-methoxypyridin-3-yl)pyridazin-3-amine

To a 20 dram vial was added6-chloro-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine(1.8 g, 6.23 mmol, 1.0 equiv), 2-methoxypyridin-3-ylboronic acid (1.0 g,6.54 mmol, 1.1 equiv), Cl₂Pd(dppf) (350 mg, 0.43 mmol, 0.07 equiv), 2Mpotassium carbonate (8 mL, 15.5 mmol, 2.5 equiv), and dioxane (21 mL).The reaction was stirred and heated to 90° C. for 2 h and then dilutedwith water (20 mL) and ethyl acetate (50 mL). After transferring to aseparatory funnel and shaking, the organic layer was separated from theaqueous layer and then washed with lithium chloride (1×20 mL). Theorganic layer was then dried over Na₂SO₄, filtered, and concentrated togive a crude solid that was purified by silica gel column chromatographyto giveN-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-6-(2-methoxypyridin-3-yl)pyridazin-3-amine(1.7 g, 77%) as an off-white solid.

6-(2-Chloropyridin-3-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine

To a 50 mL round bottom flask was addedN-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-6-(2-methoxypyridin-3-yl)pyridazin-3-amine(1.7 g, 4.7 mmol), concentrated hydrochloric acid (15 mL), and methanol(15 mL). The reaction was heated to 90° C. and stirred for 12 h. Thereaction was concentrated, brought to pH of 11 through the addition ofsaturated potassium carbonate (20 mL), and then diluted with ethylacetate (50 mL). After transferring to a separatory funnel and shaking,the organic layer was separated from the aqueous layer and washed withlithium chloride (1×20 mL). The organic layer was then dried overNa₂SO₄, filtered, and concentrated to give3-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)pyridin-2-ol(1.6 g, 95%) as a tan powder. The isolated product (1.3 g, 3.7 mmol, 1.0equiv) was transferred to a 100 mL round bottom flask, followed by theaddition of a mixture of phosphorous oxytrichloride (24 mL) and DMF (8mL). The reaction was heated to 90° C. and stirred for 6 h. The reactionwas concentrated and carefully quenched with a 50% mixture of saturatedsodium bicarbonate and lithium chloride until gas evolution ceased. Themixture was extracted with ethyl acetate (100 mL). The combined organiclayers were then dried over Na₂SO₄, filtered, concentrated, and purifiedby silica gel column chromatography to give 1.2 g (88%) of6-(2-chloropyridin-3-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amineas an off-white solid.

6-(2-Aminopyridin-3-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine

To a 5 mL microwave reaction vessel was added6-(2-chloropyridin-3-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine(750 mg, 2.0 mmol), hydrazine hydrate (1 mL), and dioxane (4 mL). Thereaction was heated in a microwave reactor to 160° C. for 15 min, thendiluted with ethyl acetate (50 mL), and washed with brine (20 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated to givea crude solid that was purified by reverse phase column chromatographyto give 150 mg ofN-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-6-(2-hydrazinylpyridin-3-yl)pyridazin-3-amineas an off-white solid. The isolated product was then dissolved inmethanol and added to a vial containing ˜1 mL of Raney Nickel suspensionin water. The mixture was then stirred under 50 psi of hydrogen for 2 h.The reaction was then filtered, concentrated, and purified by reversephase column chromatography to give 10 mg (88%) of6-(2-aminopyridin-3-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amineas an off-white solid, m/z=351.1 [M+H]

EXAMPLE 12 Preparation ofN1-(5-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-indazol-3-yl)ethane-1,2-diamine

Benzyl2-(2-Fluoro-5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamido)ethylcarbamate

To a 20 dram vial was added2-fluoro-5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzoicacid (320 mg, 0.8 mmol, 1.0 equiv), benzyl 2-aminoethylcarbamate (242mg, 1.0 mmol, 1.3 equiv), HOBt (141 mg, 1.0 mmol, 1.3 equiv), EDC HCl(200 mg, 1.0 mmol, 1.3 equiv), DIPEA (550 μL, 3.8 equiv) and CH₂Cl₂ (5mL). The reaction was stirred for 4 h and then concentrated and thenpurified using a silica gel column (50%-100% EtOAc/hexanes) to afford230 mg (50%) of benzyl2-(2-fluoro-5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamido)ethylcarbamateas a white foam.

Benzyl2-(2-fluoro-5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)phenylthioamido)ethylcarbamate

In a 20 dram vial containing benzyl2-(2-fluoro-5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamido)ethylcarbamate(230 mg, 0.5 mmol, 1 equiv) was added Lawesson's reagent (162 mg, 0.4mmol, 0.8 equiv) and dioxane (10 mL). The reaction was heated to 100° C.and stirred for 1 h, concentrated, and then purified using a silica gelcolumn (35%-100% EtOAc/hexanes) to give 203 mg (86%) of benzyl2-(2-fluoro-5-(6((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)phenylthioamido)ethylcarbamateas a pale yellow oil.

Benzyl2-(5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-indazol-3-ylamino)ethylcarbamate

The isolated benzyl2-(2-fluoro-5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)phenylthioamido)ethyl-carbamatewas transferred to a 20 dram vial, followed by the addition of hydrazinehydrate (0.1 mL) and dioxane (2 mL). The reaction was heated to 100° C.and stirred for 12 h, concentrated, and then purified using a silica gelcolumn (5%-10% MeOH/EtOAc) to yield 48 mg (25%) of benzyl2-(5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-indazol-3-ylamino)ethylcarbamateas a pale yellow oil.

N1-(5-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-indazol-3-yl)ethane-1,2-diamine

Benzyl2-(5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-indazol-3-ylamino)ethylcarbamate(48 mg, 84 μmol) was dissolved in acetonitrile (5 mL), and TMSI (0.5 mL)was added. The reaction was stirred for 15 min, diluted with methanol(15 mL), concentrated, and was directly purified by reverse phase columnchromatography to yield 20 mg (88%) ofN1-(5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-indazol-3-yl)ethane-1,2-diamineas a yellow solid, m/z=433 [M+H].

EXAMPLE 13 Preparation of6-(5-Aminopyridin-2-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine

2-Bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine

To a 25 mL round bottom flask was added 5-amino-2-bromopyridine (600 mg,3.5 mmol, 1.0 equiv), hexane-2,5-dione (420 mg, 4.2 mmol, 1.2 equiv),p-toluenesulfonic acid (5 mg), and toluene (3.5 mL). A Dean-Stark trapwas fitted on top of the round bottom flask and the reaction mixture washeated to reflux for 2 h. The reaction was then concentrated andpurified by silica gel column chromatography (5% ethyl acetate/hexanes)to give 660 mg (76%) of 2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine.

tert-Butyl-6-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

THF (8.5 mL) was cooled to −78° C. under a nitrogen atmosphere. tBuLi(1.7 mL, 2.9 mmol, 2.0 equiv) was added, followed by the addition of2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (370 mg, 1.47 mmol, 1.0equiv dissolved in 2 mL THF) over 2 min. The reaction as stirred for 45min at −78° C. Zinc chloride (510 mg, 3.75 mmol, 2.5 equiv dissolved in5 mL of THF) was added and the reaction was allowed to warm to rt andstirred for 3 h. (t-Bu₃P)₂Pd (41 mg, 0.015 mmol, 0.10 equiv dissolved in5 mL of THF) and t-butyl6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(393 mg, 0.1 mmol, 0.07 equiv dissolved in 5 mL of THF) were added andthe reaction was refluxed for 4 h followed by dilution with sodiumbicarbonate (20 mL), and extraction with ethyl acetate (40 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated to givea crude solid that was purified by silica gel column chromatography (35%EtOAc/hexanes) to give 245 mg (46%) of tert-butyl6-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.

6-(5-Aminopyridin-2-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine

To a 20 dram vial was added tert-butyl6-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(245 mg, 0.5 mmol) and a 5 mL of a 50% mixture of TFA and CH₂Cl₂. Thereaction was stirred for 15 min, concentrated, and then diluted withsodium bicarbonate (20 mL) and extracted with ethyl acetate (40 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated to givea crude solid that was purified by silica gel column chromatography (60%EtOAc/hexanes) to give 91 mg (46%) of6-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine.This product was transferred to a 100 mL round bottom flask to which wasadded hydroxylamine hydrochloride (270 mg), triethylamine (5 mL), andethanol (20 mL). The reaction mixture was heated to reflux overnight andthen concentrated, diluted with sodium bicarbonate (20 mL) and extractedwith ethyl acetate (40 mL). The organic layer was dried over Na₂SO₄,filtered, and concentrated to give a crude solid that was purified byreverse phase column chromatography to afford 28 mg of6-(5-aminopyridin-2-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine,m/z=351.2 [M+H].

EXAMPLE 14 Preparation of3-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)-4-methylpyridazin-3-yl)benzamide

6-Chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)-5-methylpyridazin-3-amine

A solution of (2-(4-fluorophenyl)-2-methylpropan-1-amine (5.5 g, 33mmol, 1.8 equiv), 3,6-dichloro-4-methylpyridazine (3.0 g, 18 mmol, 1.0equiv) and K₂CO₃ (5.1 g, 37 mmol, 2.0 equiv) in isopropanol (7.5 mL) wasstirred at 100° C. under a blanket of nitrogen for 18 hours. The cooledmixture was partitioned between water and EtOAc and the organic fractionwas concentrated in vacuo. Purification over silica gel using a 20-35%gradient of EtOAc/hexanes gave the desired product (0.80 g, 15%) of ayellow oil which was determined by HPLC to be a 5:1 mixture ofregioisomers by HPLC.

2-Fluoro-5-(6-(2-(4-fluorophenyl)-2-methylpropylamino)-4-methylpyridazin-3-yl)benzonitrile

To a solution of6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)-5-methylpyridazin-3-amine(0.8 g, 2.7 mmol, 1.0 equiv) and 2 M aqueous K₂CO₃ (2.0 mL, 8.2 mmol,3.0 equiv) in dioxane (14 mL) was added Pd(dppf)Cl₂ (0.11 g, 0.14 mmol,0.05 equiv) and 3-cyanophenylboronic acid (0.48 g, 3.3 mmol, 1.2 equiv).The mixture was stirred at 80° C. for 2 hours under a blanket ofnitrogen. This was followed by addition of another 100 mg (0.68 mmol,0.25 equiv) of the boronic acid and 30 mg (0.037 mmol, 0.013 equiv) ofPd(dppf)Cl₂ and another 1 h of heating at 100° C. The mixture wasallowed to cool to room temperature and then was diluted with EtOAc. Thesolution was washed with 50% NaCl solution, dried over Na₂SO₄ andevaporated to dryness. The residue was purified by over silica gel usinga 20-50% EtOAc/hexanes stepwise gradient to give the desired product(850 mg, 86%) as a single regioisomer.

3-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)-4-methylpyridazin-3-yl)benzamide

A 0° C. solution of2-fluoro-5-(6-(2-(4-fluorophenyl)-2-methylpropylamino)-4-methylpyridazin-3-yl)benzonitrile(0.80 g, 2.2 mmol, 1.0 equiv), 30% hydrogen peroxide (0.45 mL, 4.4 mmol,2.0 equiv), and K₂CO₃ (600 mg, 4.4 mmol, 2.0 equiv) in DMSO (9.0 mL) wasstirred for 1 hour. The mixture was diluted with EtOAc, washed withsaturated NaCl, water and saturated NaCl again, and then dried overNa₂SO₄. Purification by reverse phase HPLC using a gradient of 20-70%CH₃CN/water gave the desired product (420 mg, 51%) as a yellow solid.m/z=379.1 [M+H]+.

EXAMPLE 15 Preparation of3-(5-Cyano-6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)benzamide

3,6-Dichloropyridazine-4-carboxamide

A solution of NH₄OH (1.1 mL, 17 mmol, 1.2 equiv) anddiisopropylethylamine (6.2 mL, 36 mmol, 2.1 equiv) in THF (57 mL) wassonicated until homogeneous after which was added DMAP (1.0 g, 14 mmol,1.0 equiv). 3,6-dichloropyridazine-4-carbonyl chloride (3.0 g, 14 mmol,1.0 equiv) was then added and the solution was stirred at roomtemperature for 20 minutes. The solution was filtered and partitionedbetween EtOAc and 1 M KHSO₄ solution. The organic layer was washed oncemore with 1 M KHSO₄ and saturated NaCl, dried over Na₂SO₄, andevaporated to dryness to give the desired product (2.6 g, 96%).

6-Chloro-3-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-4-carboxamide

Using a similar procedure as was used for6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)-5-methylpyridazin-3-aminein example 14, 3,6-dichloropyridazine-4-carboxamide (2.6 g, 13 mmol, 1.0equiv), (2-(4-fluorophenyl)-2-methylpropan-1-amine (2.5 g, 15 mmol, 1.1equiv), and diisopropylethylamine (2.8 mL, 16 mmol, 1.2 equiv) in CH₃CN(54 mL) was heated at 60-90° C. for 48 hours. The product was purifiedover silica gel with 100% EtOAc to give the desired product (3.4 g, 78%)as a yellow foamy solid.

6-Chloro-3-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-4-carbonitrile

To a portion of6-chloro-3-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-4-carboxamide(3.4 g, 11 mmol, 1.0 equiv) was added POCl₃ (10 mL) at room temperature.The mixture was stirred at reflux for 3 hours and then quenched bypouring it into ice water containing NaHCO₃. Dioxane and EtOAc wereadded to facilitate mixing of the layers. The layers were allowed toseparate and the aqueous layer was extracted with EtOAc and the combinedorganic phases were washed with saturated NaCl. The organics were driedover Na₂SO₄ and evaporated to dryness in vacuo. Purification over silicagel using a gradient of 10-20% EtOAc/hexanes yielded the desired product(0.60 g, 19%) as a yellow oil.

3-(5-Cyano-6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)benzamide

To a solution of6-chloro-3-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-4-carbonitrile(550 mg, 1.8 mmol, 1.0 equiv), 3-aminocarbonylphenylboronic acid,pinacol ester (330 mg, 2.0 mmol, 1.1 equiv) and aqueous K₂CO₃ (2.0 M,5.0 mL, 5.4 mmol, 3.0 equiv) in dioxane (18 mL) was added Pd(dppf)Cl₂(150 mg, 0.18 mmol, 0.1 equiv). The mixture was stirred at 120° C. for10 minutes in a microwave and allowed to cool to room temperature. Thesolvents were evaporated in vacuo, and the residue was dissolved indichloromethane. The solution was filtered and the solvent dried overNa₂SO₄. Purification over silica gel using a gradient of 40-80%EtOAc/hexanes gave a yellow solid that was slurried with CH₃CN to givethe desired product (30 mg, 4.3%) as a yellow solid. m/z=390.2 [M+H]+.

EXAMPLE 16 Preparation of (S)-2-(4-Fluorophenyl)propan-1-amine

(S)-4-Benzyl-3-(2-(4-fluorophenyl)acetyl)oxazolidin-2-one

To a cooled (−78° C.) solution of (S)-4-benzyloxazolidin-2-one (10 g, 58mmol, 1.0 equiv) in 100 mL THF was added dropwise n-BuLi (40 mL, 1.6 Min hexanes, 64 mmol, 1.1 equiv). After stirring for 30 minutes,4-fluorophenylacetyl chloride (10 g, 0.58 mmol, 1.0 equiv) was addeddropwise. After stirring for an additional 30 minutes, the reactionmixture was allowed to warm to room temperature. The reaction wasquenched with saturated aq. NH₄Cl, extracted with dichloromethane, andwashed with brine. The organic layer was then dried over sodium sulfate,filtered, and concentrated in vacuo. Purification by silica gel (10-20%EtOAc/hexanes) provided the title compound as a thick oil (14.7 g, 81%).

(S)-4-Benzyl-3((S)-2-(4-fluorophenyl)propanoyl)oxazolidin-2-one

To a room-temperature solution of(S)-4-benzyl-3-(2-(4-fluorophenyl)acetyl)oxazolidin-2-one (5.1 g, 16.3mmol, 1.0 equiv) in dry THF (100 mL) was added iodomethane (1.0 mL, 16.2mmol, 1.0 equiv) by syringe. The resulting mixture was cooled to −78°C., and NaHMDS (8.15 mL, 2M in THF, 16.3 mmol, 1.0 equiv) was addeddropwise by syringe. After stirring for 15 minutes at −78° C., thereaction mixture was allowed to warm to room temperature. The reactionwas quenched with saturated aq. NH₄Cl, and diluted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by silica gel chromatography (7-20%EtOAc/hexanes) provided the title compound (2.6 g, 49%).

(S)-2-(4-Fluorophenyl)propan-1-ol

To a room-temperature solution of(S)-4-benzyl-3-((S)-2-(4-fluorophenyl)propanoyl)oxazolidin-2-one (1.8 g,5.5 mmol, 1.0 equiv) in THF (18 mL) was added a solution of NaBH₄ (1.0g, 26.4 mmol, 4.8 equiv) in water (6.0 mL). The reaction mixture wasstirred for 3 h at room temperature and then quenched by the carefuladdition of aq. 1 M HCl. The reaction mixture was diluted with water andethyl acetate. The layers were separated and the organic layer wassubsequently washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by silica gel chromatography (10-75%EtOAc/Hexanes) provided the title compound (0.824 g, 97%).

(S)-2-(2-(4-Fluorophenyl)propyl)isoindoline-1,3-dione

To a solution of (S)-2-(4-fluorophenyl)propan-1-ol (0.82 g, 5.35 mmol,1.0 equiv), phthalimide (0.82 g, 5.6 mmol, 1.05 equiv), and triphenylphosphine (2.1 g, 8.03 mmol, 1.5 equiv) in dry THF (18 mL) was addeddropwise diethylazodicarboxylate (3.6 mL, 15% in toluene, 8.0 mmol, 1.5equiv). The reaction mixture was stirred over 72 h and then concentratedin vacuo. Purification by silica gel chromatography (15-25%EtOAc/Hexanes) provided the title compound (0.9 g, 59%).

(S)-2-(4-Fluorophenyl)propan-1-amine

To a room-temperature solution of(S)-2-(2-(4-fluorophenyl)propyl)isoindoline-1,3-dione (900 mg, 3.2 mmol,1.0 equiv) in toluene (14 mL) was added hydrazine hydrate (1.4 mL, 45mmol, 14 equiv) by syringe. The resulting mixture was heated to 80° C.for 30 minutes and then cooled to room temperature. The resultingsolution was decanted from the solid in the reaction mixture, and thesolid was washed with additional toluene. The combined organic layerswere combined and concentrated in vacuo to provide the title compound(491 mg, 99%), which was used without further purification.

EXAMPLE 17 Preparation of 2-(4-Fluorophenyl)-2-methylpropan-1-amine

To a solution of 4-fluorophenylacetonitrile (50 g, 370 mmol, 1.0 equiv)and iodomethane (70 mL, 1.1 mol, 3 equiv) in THF (370 mL) was addedKOt-Bu (124 g, 1.1 mol, 3 equiv) as a solid in portions such that thereaction mixture did not exceed 50° C. The reaction mixture was stirredovernight and then quenched by the addition of brine. The mixture wasdiluted with EtOAc and washed twice with brine. The organic layer wasdried over Na₂SO₄, filtered, and concentrated in vacuo to provide2-(4-fluorophenyl)-2-methylpropanenitrile as a yellow oil (57 g, 94%),which was used without further purification in the next step. To asolution of the nitrile in dry THF (800 mL) was added a solution oflithium aluminum hydride (210 mL, 2 M in ether, 420 mmol, 1.2 equiv).After the mixture was heated at reflux overnight, the reaction wasallowed to cool to room temperature, and a Fieser and Fieser work-up(300 uL water/mmol, 1.0 mL 3N NaOH/mmol, 300 uL water/mmol) wasperformed. Filtration of the resulting solids provided the titlecompound as an orange oil (57 g, 92%).

EXAMPLE 18 Preparation (1-(4-Fluorophenyl)cyclobutyl)methanamine

A solution of 4-fluorophenylacetonitrile (6.7 g, 75 mmol, 1.5 equiv),1,3-dibromopropane (10 mL, 50 mmol, 1 equiv), KOH (27 g, 150 mmol, 3.0equiv), and tetrabutylammonium bromide (100 mg) in toluene (135 mL) washeated to 100° C. for 3 hours. The organic layer was separated andconcentrated to dryness. Silica gel chromatography using a gradient of0-30% EtOAc/hexanes resulted in partially purified product which wasfurther purified by Kugelrohr distillation at 200° C. to provide 3.76 g(22 mmol) of the intermediate nitrile product as an oil. The residue wasdissolved in dry THF (22 mL) and treated with a solution of LAH (27 mL,2 M in ether, 55 mmol, 2.5 equiv). The mixture was stirred at 0° C. for2 hours followed by a Fieser and Fieser work-up (38 uL water/mmol, 118uL 3N NaOH/mmol, 38 uL water/mmol). The organic layer was concentratedto dryness to provide the desired product (3.6 g, 40% overall) as ayellow oil.

EXAMPLE 19 Preparation of(1-(6-Methoxypyridin-2-yl)cyclobutyl)methanamine

1-(6-Fluoropyridin-2-yl)cyclobutanecarbonitrile

Following the same procedure as described for2-(3-fluoropyridin-2-yl)acetonitrile (Example 18), 2,6-difluoropyridine(5.0 g, 43 mmol, 1.0 equiv), cyclobutylcarbonitrile (3.5 g, 43 mmol, 1.0equiv) and NaHMDS (2.0 M in THF, 24 mL, 47 mmol, 1.1 equiv) in toluene(100 mL) gave the desired product (4.9 g, 64%) as a colorless oilfollowing purification over silica gel using 25% EtOAc/hexanes aseluent.

1-(6-Methoxypyridin-2-yl)cyclobutanecarbonitrile

To stirred 6.0 mL of anhydrous methanol at 0° C. under nitrogen wasadded sodium metal (˜1 g) and the mixture stirred for 30 minutes. Tothis was added 1-(6-fluoropyridin-2-yl)cyclobutanecarbonitrile (1.6 g,9.1 mmol) and the resulting mixture heated to 75° C. for 45 minutes. Thesolution was cooled to room temperature and partitioned between waterand EtOAc. The layers were separated, the aqueous phase was extractedwith EtOAc, and the combined organic phases were washed with saturatedNaCl, dried over Na₂SO₄ and concentrated in vacuo to give the desiredproduct (1.7 g, 97%) as a colorless oil.

(1-(6-Methoxypyridin-2-yl)cyclobutyl)methanamine

To a stirred solution of1-(6-methoxypyridin-2-yl)cyclobutanecarbonitrile (1.7 g, 8.8 mmol, 1.0equiv) in THF (20 mL) was added lithium aluminum hydride solution (1.0 Min THF, 11 mL, 11 mmol, 1.1 equiv). The mixture was refluxed for 1.5hours and allowed to cool to room temperature. Water (0.43 mL) was addedslowly followed by 0.43 mL of 3 M NaOH and then three additions of 0.43mL of water (Fieser and Fieser workup). The resulting mixture wasfiltered through diatomaceous earth and rinsed with THF. The combinedorganics were dried over Na₂SO₄ and concentrated to dryness to give thedesired product (1.6 g, 97%) as a viscous oil.

EXAMPLE 20 Preparation of 1-(3-Fluoropyridin-2-yl)cyclobutanamine

1-(3-Fluoropyridin-2-yl)cyclobutanecarboxamide

To a 250 mL round bottom flask containing DMSO (60 mL),1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile (2.96 g, 16.8 mmol, 1.0equiv) was added and the mixture was stirred until homogenous. Potassiumcarbonate (7.0 g, 50.4 mmol, 3.0 equiv) was then added and the reactionmixture was cooled to 0° C., followed by the addition of 35% hydrogenperoxide (6.5 mL). The reaction was stirred at 0° C. for 30 min and thenwarmed to room temperature. At this time, the reaction was diluted withwater (50 mL) and ethyl acetate (100 mL). After transferring to aseparatory funnel and shaking, the organic layer was separated from theaqueous layer and then washed with brine (3×50 mL). The organic layerwas then dried over Na₂SO₄, filtered, and concentrated to give a crudesolid that was purified by silica gel chromatography (10% EtOAC/hexanes)to afford 1.92 g (59%) of 1-(3-fluoropyridin-2-yl)cyclobutanecarboxamideas a white solid.

Methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate

1-(3-fluoropyridin-2-yl)cyclobutanecarboxamide (1.92 g, 9.88 mmol, 1.0equiv) was dissolved in methanol (20 mL) and potassium hydroxide (1.11g, 19.8 mmol, 2.0 equiv) was added. The mixture was sonicated untilhomogeneous, followed by the addition of iodosobenzene diacetate (4.77g, 14.8 mmol, 1.5 equiv). The reaction was stirred for 20 min and thendiluted with water (100 mL) and ethyl acetate (125 mL). Aftertransferring to a separatory funnel and shaking, the organic layer wasseparated from the aqueous layer, and the aqueous layer was extractedwith EtOAc (50 mL). The combined organic layers were then dried overNa₂SO₄, filtered, and concentrated to give a crude oil that was purifiedby silica gel chromatography (40% EtOAC/hexanes) to afford 1.47 g (67%)of methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate as a white solid.

1-(3-Fluoropyridin-2-yl)cyclobutanamine

To a 20 mL microwave reaction vial was added methyl1-(3-fluoropyridin-2-yl)cyclobutylcarbamate (1.47 g, 6.56 mmol), ethanol(12 mL) and 3N aqueous sodium hydroxide (7 mL). The reaction mixture washeated in the microwave reactor at 150° C. for 30 min. The ethanol wasevaporated under reduced pressure and the mixture was extracted withethyl acetate (30 mL). The aqueous layer was then extracted with ethylacetate (2×30 mL). The organic layers were combined, dried over Na₂SO₄,filtered, and concentrated to give1-(3-fluoropyridin-2-yl)cyclobutanamine (1.01 g, 93%) as a crude yellowoil that was used in the next reaction step without further purification

EXAMPLE 21 Preparation of 2-(3-Fluoropyridin-2yl)acetonitrile

To a 0° C. solution of 2-chloro-3-fluoropyridine (3.0 g, 23 mmol, 1.0equiv) and acetonitrile (1.3 mL, 25 mmol, 1.1 equiv) in toluene (50 mL)was added sodium hexamethyldisilazide (NaHMDS) (2.0 M in THF, 13 mL, 25mmol, 1.1 equiv). The resulting mixture was stirred for 2 hours at 0° C.and then partitioned between EtOAc and water. The aqueous layer wasextracted with EtOAc and the combined organic phases were washed withsaturated NaCl, dried over Na₂SO₄ and concentrated in vacuo to providethe crude desired product as an oil which was used without furtherpurification.

EXAMPLE 22 Preparation of6-Chloro-N-(2-phenylpropan-2-yl)pyridazin-3-amine

To a 5 mL microwave reaction vial was added 3,6-dichloropyridazine (544mg, 3.7 mmol, 1.0 equiv), cumylamine (500 mg, 3.7 mmol, 1.0 equiv), andDIPEA (640 μL, 3.7 mmol, 1.0 equiv). The reaction was heated in amicrowave reactor to 225° C. for 15 min and then diluted with brine (20mL) and extracted with ethyl acetate (40 mL). The organic layer wasdried over Na₂SO₄, filtered, and concentrated to give a crude solid thatwas purified by silica gel column chromatography (20% EtOAc/hexanes) toyield 48 mg (5%) of 6-chloro-N-(2-phenylpropan-2-yl)pyridazin-3-amine asa white solid.

EXAMPLE 23 Preparation of2-(2-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)acetamide

5-((t-Butyldimethylsilyloxy)methyl)thiazole

Thiazole-5-methanol (65 g, 0.56 mol), imidazole (58 g, 0.85 mol), andCH₂Cl₂ (700 mL) were added to a round bottom flask, followed by TBSCI(93 g, 0.62 mol). The reaction was stirred for 20 min and the resultantwhite solid was filtered off. The filtrate was washed with saturatedsodium bicarbonate, dried over sodium sulfate, concentrated, andpurified by silica gel chromatography (10% EtOAC/hexanes) to afford 140g of 5-((t-butyldimethylsilyloxy)methyl)thiazole as a clear oil.

t-butyl6-(5-((t-butyldimethylsilyloxy)methyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

To a stirring mixture of THF (2000 mL) and diisopropylamine (79.3 mL,0.56 mol) at −78° C. was added n-BuLi (244 mL, 0.56 mol) dropwise. Afterstirring for 20 min at −78° C., a solution of5-((t-butyldimethylsilyloxy)methyl)thiazole (110.9 g, 0.49 mol in 300 mLof THF) was added dropwise to the reaction mixture while maintaining atemperature less than −70° C. After the addition was complete, thereaction was stirred for an additional 30 min and a solution of zincbromide (126.6 g, 0.56 mol in 300 mL of THF) was added dropwise to thereaction mixture while maintaining a temperature less than −65° C. Thereaction was warmed to 0° C., stirred for 30 min, and added to astirring mixture of t-butyl6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(100 g, 0.26 mol), tetrakis(triphenylphosphine)palladium(0) (56 g, 0.05mol), and THF (2000 mL) heated to 80° C. The reaction mixture wasstirred overnight at 80° C. The reaction was concentrated and thenslurried in ethyl acetate and brine. The resultant solid was filteredoff, and the filtrate was dried over sodium sulfate, concentrated, andpurified twice by silica gel chromatography (EtOAc/hexanes) to afford112.5 g of t-butyl6-(5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamateas a dark oil.

t-butyl(1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-(hydroxymethyl)thiazol-2-yl)pyridazin-3-yl)carbamate

To a solution of t-butyl6-(5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(112.5 g, 0.19 mol) in THF (1000 mL) was added TBAF (105 mL, 0.29 mol,75% w/w). The reaction was stirred for 30 min followed by the additionof ammonium chloride (200 mL). The organic layer was separated, washedwith brine (300 mL×3), and concentrated (this wash was repeated once).Ethyl acetate was added to the oil, resulting in a white solid.Filtration of the solid afforded 44 g of t-butyl(1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-(hydroxymethyl)thiazol-2-yl)pyridazin-3-yl)carbamate.

t-butyl6-(5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

To a solution of t-butyl(1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-(hydroxymethyl)thiazol-2-yl)pyridazin-3-yl)carbamate(44.1 g, 93.8 mmol) in dioxane (235 mL) was added thionyl chloride (27.3mL, 375.3 mmol). The reaction was stirred until it was homogeneous. Thereaction was then slowly quenched by pouring into a mixture of saturatedpotassium carbonate solution and ethyl acetate. The organic layer wasthen separated, dried over Na₂SO₄, filtered, concentrated, and purifiedby silica gel chromatography (EtOAC/hexanes) to afford 33.1 g of t-butyl6-(5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamateas a white solid.

t-butyl6-(5-(cyanomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

To a solution of t-butyl6-(5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(33.1 g, 68 mmol) in CH₂Cl₂ (450 mL) was added tetrabutylammoniumcyanide (36 g, 135 mmol). The reaction was heated to 45° C. and stirredfor 1 h, followed by concentration and purification by silica gelchromatography (EtOAc/hexanes) to afford 13.4 g of t-butyl6-(5-(cyanomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamateas an off-white solid.

2-(2-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)acetamide

To a solution of t-butyl6-(5-(cyanomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(12.5 g, 26.0 mmol) in DMSO (260 mL) was added potassium carbonate (14.4g, 104.1 mmol). The mixture was cooled to 0° C. and hydrogen peroxide(86 mL) was slowly added. The reaction was warmed to rt and stirred for90 min. The reaction was diluted with EtOAc (200 mL) and water (500 mL),and the organic layer was washed three times with brine (150 mL). Theorganic layer was then dried over Na₂SO₄, filtered, and concentrated togive a crude solid that was purified by silica gel chromatography(CH₃CN/CH₂Cl₂) to afford 6.2 g of t-butyl6-(5-(2-amino-2-oxoethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamateas a reddish solid. This compound was combined with other batches (15.5g overall), dissolved in 25% TFA/CH₂Cl₂, and stirred for 1 h. Thereaction was then concentrated, dissolved in ethyl acetate (75 mL), andwashed three times with potassium carbonate. The organic layer was thendried over Na₂SO₄, filtered, and concentrated to give a crude solid thatwas recrystallized with THF to give 10.8 g of1-(2-((-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyrimidin-5-yl)-1H-pyrrole-3-carboxamideas an off-white solid (M+H=399.1).

EXAMPLE 24 Preparation of2-(2-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)-N-methylacetamide

A solution of t-butyl6-(5-(cyanomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(1 g, 2 mmol) in HCl (30 mL, conc) was heated to 105° C. in a microwavereactor and stirred for 15 min. The reaction was concentrated to give900 mg (2.3 mmol) of a crude reddish solid. To this solid was addedmethylamine hydrochloride (183 mg, 2.7 mmol), HOBt (365 mg, 2.7 mmol),EDC (516 mg, 2.7 mmol), DMF (30 mL), and TEA (1.3 mL, 9 mmol). Thereaction was stirred at rt overnight. The reaction was then poured intoethyl acetate (200 mL), washed with water (3×100 mL), and the organiclayer was separated, dried over Na₂SO₄, filtered, concentrated, andrecrystallized from EtOAc to give 408 mg of2-(2-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)-N-methylacetamideas a white solid (M+H=413.3).

EXAMPLE 25 Preparation ofN-((2-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)methyl)-2-hydroxyacetamide

t-butyl6-(5-(Azidomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

To a stirring solution of t-butyl6-(5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(60.7 g, 124 mmol) in DMF (800 mL) was added sodium azide (22.2 g, 341mmol) and DIPEA (31.1 mL, 171 mmol). The reaction was heated to 60° C.and stirred for 1 h. The reaction was poured into ethyl acetate (2000mL), washed with water (3×400 mL), and the combined organic layers wereseparated, dried over Na₂SO₄, filtered, concentrated, and purified bysilica gel chromatography (EtOAC/hexanes) to afford 20.0 g of t-butyl6-(5-(azidomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamateas a yellow oil.

t-butyl6-(5-(Aminomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

Tin(II) chloride dihydrate (15.5 g, 80 mmol) was added to a solution oft-butyl6-(5-(azidomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(20 g, 40 mmol) in methanol (400 mL) and the reaction was stirred at rtfor 30 min. The reaction was poured into ethyl acetate (1000 mL), washedwith water (3×200 mL), and the combined organic layers were separated,dried over Na₂SO₄, filtered, concentrated, and purified using silica gelcolumn chromatography (9% MeOH/90% EtOAc/1% TEA) to give 35 g of t-butyl6-(5-(aminomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamateas a yellow oil.

N-((2-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)methyl)-2-hydroxyacetamide

t-butyl6-(5-(aminomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(4.8 g, 10 mmol), glycolic acid (0.9 g, 12 mmol), HOBt (1.6 g, 12 mmol),EDC (2.3 g, 12 mmol), DMF (50 mL), and TEA (5.9 mL) were added to a 250mL round bottom flask and the reaction was heated to 60° C. and stirredfor 1 h. The reaction was poured into ethyl acetate (400 mL), washedwith water (3×100 mL), and the combined organic layers were separated,dried over Na₂SO₄, filtered, concentrated, and purified by silica gelchromatography (EtOAC/hexanes) to afford 3.9 g of t-butyl(1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-((2-hydroxyacetamido)methyl)thiazol-2-yl)pyridazin-3-yl)carbamateas a white solid. This compound was dissolved in 30% TFA/CH₂Cl₂ (30 mL)and stirred for 1 h. The reaction was concentrated, dissolved in EtOAc(200 mL), washed with potassium carbonate (3×30 mL), concentrated, andthen recrystallized with ethanol to give a white solid that was furtherpurified with reverse phase chromatography to give 305 mg ofN-((2-(6((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)methyl)-2-hydroxyacetamideas a white solid (M+H=429.1).

EXAMPLE 26 Preparation of1-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-pyrrole-3-carboxamide

t-butyl6-(3-Cyano-1H-pyrrol-1-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

To a stirring solution of t-butyl6-fluoropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(200 mg, 551 μmol) in DMF (2 mL) was added 3-cyanopyrrole (61 mg, 661μmol) and potassium carbonate (152 mg, 1.1 mmol). The reaction washeated to 110° C. and stirred for 30 min. The reaction was then pouredinto ethyl acetate (100 mL), washed with water (3×25 mL), and theorganic layer was separated, dried over Na₂SO₄, filtered, concentrated,and purified by silica gel chromatography (EtOAC/hexanes) to afford 130mg of t-butyl6-(3-cyano-1H-pyrrol-1-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamateas a pale yellow solid.

1-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-pyrrole-3-carboxamide

t-butyl6-(3-cyano-1H-pyrrol-1-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(120 mg, 267 μmol), potassium carbonate (147 mg, 1.1 mmol), and DMSO (3mL) were combined in a vial and cooled to 0° C. Hydrogen peroxide (700uL) was added dropwise, and the reaction was warmed to rt and stirredfor 1 h. The reaction was then poured into ethyl acetate (50 mL), washedwith water (3×20 mL), and the organic layer was separated, dried overNa₂SO₄, filtered, and concentrated. The crude solid was dissolved in 50%TFA/CH₂Cl₂ (2 mL) and stirred for 30 min. The reaction was thenconcentrated and purified using reverse phase chromatography to give 29mg of1-(6((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-pyrrole-3-carboxamideas a tan solid (M+H=367.1).

EXAMPLE 27 Preparation of2-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxamide

t-butyl6-Cyanopyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

To a solution of6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3-carbonitrile(3.3 g, 4.7 mmol) in THF (30 mL) was added di-t-butyl dicarbonate (2.8g, 13 mmol), and DMAP (0.5 g, 4.3 mmol). The reaction mixture wasrefluxed for 2 h. The reaction was concentrated and then poured intoethyl acetate (150 mL) and washed with 0.1 M HCl (50 mL, aq) and brine(50 mL). The organic layer was separated, dried over Na₂SO₄, filtered,and concentrated to give a crude oil that was purified by silica gelcolumn chromatography (EtOAC/hexanes) to afford 3.9 g of t-butyl6-cyanopyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamateas a white solid.

t-butyl6-Carbamothioylpyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

NMP (40 mL) and DIPEA (10 mL) were added to t-butyl6-cyanopyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(3.9 g, 10 mmol), and hydrogen sulfide was bubbled through the reactionmixture for 2 h. The reaction was diluted with water, and the resultantyellow solid was filtered and dried under vacuum to give 2.1 g oft-butyl6-carbamothioylpyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamateas a yellow solid.

Ethyl2-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxylate

t-Butyl6-carbamothioylpyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(1.0 g, 2.4 mmol), diethylbromomalonate (2 mL, 12 mmol), and toluenewere added to a round bottom flask, heated to 90° C., and stirred for 40min. The reaction was concentrated and purified using reverse phasechromatography to yield 219 mg of ethyl2-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxylateas an off-white solid.

2-(6-(t-Butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-methoxy-2,5-dihydrothiazole-5-carboxylicacid

To a stirring solution of ethyl2-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxylate(350 mg, 0.7 mmol) in DMF (4 mL) was added methyl iodide (200 μL, 3.3mmol) and sodium hydride (60% dispersion in mineral oil, 40 mg, 1 mmol).The reaction was stirred at rt for 1 h and at 40° C. for 45 min. Thereaction was then concentrated and quenched with water (5 mL), pouredinto ethyl acetate (150 mL), and washed with 0.1 M HCl (50 mL, aq) andbrine (50 mL). The organic layer was separated, dried over Na₂SO₄,filtered, concentrated and purified by silica gel column chromatography(EtOAC/hexanes) to afford 205 mg of ethyl2-(6-(tert-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-methoxy-2,5-dihydrothiazole-5-carboxylate.This compound was dissolved in methanol (4 mL) and 1M KOH (aq, 2 mL).The reaction mixture was heated to 75° C. and stirred for 45 min. Thereaction was cooled and the pH was adjusted to 4 using 1M HCl. Thereaction was then poured into ethyl acetate (50 mL), washed with brine(15 mL), dried over Na₂SO₄, filtered, and concentrated to give 175 mg of2-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-methoxy-2,5-dihydrothiazole-5-carboxylicacid as a white foam.

t-butyl6-(5-Carbamoyl-4-methoxy-2,5-dihydrothiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

To a 50 dram vial was added2-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-methoxy-2,5-dihydrothiazole-5-carboxylicacid (175 mg, 0.34 mmol), HATU (194 mg, 0.51 mmol), HOAt (70 mg, 0.51mmol), DIPEA (296 μL, 1.7 mmol), NMP (2 mL), and ammonium chloride (180mg, 3.4 mmol). The reaction was stirred overnight at rt. The reactionwas then poured into ethyl acetate (50 mL), washed with aqueous sodiumbicarbonate, and brine (50 mL). The organic layer was separated, driedover Na₂SO₄, filtered, concentrated and purified by silica gel columnchromatography (EtOAC/hexanes) to afford 120 mg of t-butyl6-(5-carbamoyl-4-methoxy-2,5-dihydrothiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.

2-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxamide

To a stirring mixture of t-butyl6-(5-carbamoyl-4-methoxy-2,5-dihydrothiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(60 mg, 0.12 μmol) in CH₂Cl₂ (2 mL) was added BBr₃ (140 μL, 1.2 mmol).The reaction was stirred at rt for 2 h and then at 60° C. for 15 min.The reaction was cooled to rt and carefully diluted with methanol (2mL). The reaction was concentrated, diluted with ethyl acetate (20 mL),and saturated sodium bicarbonate (10 mL) was added. The mixture wasagitated and then filtered. The subsequent crude solid was then purifiedusing reverse phase chromatography to give 15 mg of2-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxamideas a yellow solid (M+H=401.3)

EXAMPLE 28 Preparation of4-fluoro-3-(6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-2-hydroxybenzamide

t-butyl6-(3-Bromo-6-fluoro-2-methoxyphenyl)pyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

t-Butyl6-Bromopyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(3.0 g, 6.61 mmol), 3-bromo-6-fluoro-2-methoxyphenylboronic acid (1.64g, 6.61 mmol), (dppf)PdCl₂ (0.48 g, 0.66 mmol), nitrogen-sparged dioxane(13.2 mL) and aq. 2 N K₂CO₃ (0.6 mL) were combined and heated in amicrowave reactor at 125° C. The reaction mixture was diluted with EtOAcand washed with satd. aq. NaHCO₃ and brine. The organic layer was driedover sodium sulfate, filtered, and concentrated. Silica gelchromatography afforded the title compound as a yellow solid (1.4 g,37%), (m/z [M+H]=579.1).

t-butyl6-(3-cyano-6-fluoro-2-methoxyphenyl)pyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

t-Butyl6-(3-Bromo-6-fluoro-2-methoxyphenyl)pyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(1.4 g, 3.0 mmol), zinc cyanide (0.42 g, 3.6 mmol), Pd(PPh₃)₄ (1.0 g,0.9 mmol), DMF (3 mL) were combined and heated to 100° C. The reactionmixture was diluted with EtOAc and washed with satd. aq. NaHCO₃ andbrine. The organic layer was dried over sodium sulfate, filtered, andconcentrated. Silica gel chromatography afforded the title compound as ayellow solid (1.0 g, 63%), (m/z [M+H]=526.2).

t-butyl6-(3-carbamoyl-6-fluoro-2-methoxyphenyl)pyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

t-Butyl6-(3-cyano-6-fluoro-2-methoxyphenyl)pyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(1.0 g, 1.9 mmol), K₂CO₃ (0.8 g, 5.8 mmol), and DMSO (10 mL) werecombined in a round bottom flask, cooled to 0° C., and H₂O₂ (2 mL of 35%solution) was added dropwise. The reaction mixture was diluted withEtOAc and washed with satd. aq. NaHCO₃ and brine. The organic layer wasdried over sodium sulfate, filtered, and concentrated. Silica gelchromatography afforded the title compound as a white solid (0.32 g,33%), (m/z [M+H]=545.1).

4-Fluoro-3-(6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-2-hydroxybenzamide

t-Butyl6-(3-carbamoyl-6-fluoro-2-methoxyphenyl)pyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(0.32 g, 0.59 mmol), lithium iodide (0.71 g, 5.34 mmol), and pyridine (5mL) were combined in a microwave reactor and heated to 125° C. Thereaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO₃and brine. The organic layer was dried over sodium sulfate, filtered,and concentrated. Reverse phase chromatography provided4-fluoro-3-(6-(((E)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-2-hydroxybenzamideas a white solid (0.024 g, 10%), (m/z [M+H]=430.1).

EXAMPLE 29 Preparation of4-fluoro-5-(6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-2-hydroxybenzamide

t-Butyl6-(5-bromo-2-fluoro-4-methoxyphenyl)pyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

t-Butyl6-bromopyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(3.0 g, 6.61 mmol),2-(5-bromo-2-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.2 g, 6.61 mmol), (dppf)PdCl₂ (0.48 g, 0.66 mmol), nitrogen-spargeddioxane (13.2 mL) and aq. 2 N K₂CO₃ (0.6 mL) were combined and heated to90° C. The reaction mixture was diluted with EtOAc and washed with satd.aq. NaHCO₃ and brine. The organic layer was dried over sodium sulfate,filtered, and concentrated. Silica gel chromatography provided a lightyellow solid (1.7 g, 44%), (m/z [M+H]=579.1).

t-Butyl6-(5-cyano-2-fluoro-4-methoxyphenyl)pyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

t-Butyl6-(5-bromo-2-fluoro-4-methoxyphenyl)pyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(1.7 g, 3.6 mmol), zinc cyanide (0.51 g, 4.3 mmol), Pd(PPh₃)₄ (1.26 g,1.0 mmol), DMF (5 mL) were combined and heated to 100° C. The reactionmixture was diluted with EtOAc and washed with satd. aq. NaHCO₃ andbrine. The organic layer was dried over sodium sulfate, filtered, andconcentrated. Silica gel chromatography provided a yellow solid (1.1 g,66%), (m/z [M+H]=526.2).

t-Butyl6-(5-carbamoyl-2-fluoro-4-methoxyphenyl)pyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

t-Butyl6-(5-cyano-2-fluoro-4-methoxyphenyl)pyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(0.21 g, 0.4 mmol), K₂CO₃ (0.22 g, 1.6 mmol), and DMSO (4 mL) werecombined in a round bottom flask, cooled to 0° C., and H₂O₂ (1.3 mL of35%) was added dropwise. The reaction mixture was diluted with EtOAc andwashed with satd. aq. NaHCO₃ and brine. The organic layer was dried oversodium sulfate, filtered, and concentrated. Silica gel chromatographyprovided a white solid (0.10 g, 46%), (m/z [M+H]=545.1).

4-Fluoro-5-(6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-2-hydroxybenzamide

t-Butyl6-(5-carbamoyl-2-fluoro-4-methoxyphenyl)pyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(0.10 g, 0.18 mmol), lithium iodide (0.22 g, 1.65 mmol) and pyridine (3mL) were combined in a microwave reactor and heated to 125° C. Thereaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO₃and brine. The organic layer was dried over sodium sulfate, filtered,and concentrated. Reverse phase chromatography provided the titlecompound as a white solid (0.023 g, 30%), (m/z [M+H]=430.1).

EXAMPLE 30 Preparation of5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-pyrazole-3-carboxamide

t-Butyl641-ethoxyvinyl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

t-Butyl6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(5.1 g, 13.0 mmol), tributyl(1-ethoxyvinyl)stannane (6.1 g, 16.9 mmol),(PPh₃)₂PdCl₂ (2.3 g, 3.2 mmol), and nitrogen-sparged dioxane (18 mL)were combined and heated in a microwave reactor at 150° C. The reactionmixture was diluted with EtOAc and washed with satd. aq. NaHCO₃ andbrine. The organic layer was dried over sodium sulfate, filtered, andconcentrated. Silica gel chromatography provided a light yellow solid(3.9 g, 71%), (m/z [M+H]=429.2).

t-Butyl6-acetylpyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

t-Butyl6-(1-ethoxyvinyl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(1.0 g, 2.3 mmol), EtOH (75 mL), and 1 N HCl (15 mL) were combined at 0°C., warmed to 25° C., and stirred for 1 h. The reaction mixture wasconcentrated and silica gel chromatography provided a colorless oil (0.6g, 64%), (m/z [M+H]=401.1).

Ethyl5-(6-(tert-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-1H-pyrazole-3-carboxylate

t-Butyl6-acetylpyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(2.5 g, 6.2 mmol) in THF (150 mL) was treated with NaOEt (3.44 g, 10.6mmol, 21% in EtOH). The resulting mixture was then treated with diethyloxalate (1.7 mL, 12.5 mmol), heated to 45° C., and stirred for 4 h. Thereaction mixture was added to 1 N HCl, extracted with EtOAc, and washedwith satd. aq. NaHCO₃ and brine. The organic layer was dried over sodiumsulfate, filtered, and concentrated. A portion of the resultant oil wasdissolved in AcOH and hydrazine (0.41 g, 13.2 mmol) was added andstirred at 80° C. Concentration afforded a yellow oil which was purifiedby reverse-phase chromatography to give solid (0.285 g, 62%), (m/z[M+H]=497.2).

5-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-pyrazole-3-carboxamide

Ethyl5-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-1H-pyrazole-3-carboxylate(0.28 g, 0.56 mmol) and 7N ammonia in MeOH were combined in a microwavereactor and heated to 110° C. for 1 h. The reaction mixture was thenconcentrated, diluted with EtOAc, and washed with satd. aq. NaHCO₃ andbrine. The organic layer was dried over sodium sulfate, filtered, andconcentrated. The resultant oil was diluted in 10 mL of DCM and TFA (15mL) was added. The reaction mixture was then concentrated and purifiedby reverse phase chromatography to give the title compound as a whitesolid (18 mg, 12%), (m/z [M+H]=368.1).

EXAMPLE 31 Preparation of3-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)isoxazole-5-carboxamide

t-Butyl(1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-vinylpyridazin-3-yl)carbamate

t-Butyl6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(2.5 g, 6.36 mmol), triethenylboroxin pyridine complex (1.0 g, 4.13mmol), Pd(PPh₃)₄ (0.3 g, 0.25 mmol), nitrogen-sparged dioxane (13.2 mL)and aq. 2 N K₂CO₃ (0.9 mL) were combined and heated to 110° C. for 25min. The reaction mixture was diluted with EtOAc and washed with satd.aq. NaHCO₃ and brine. The organic layer was dried over sodium sulfate,filtered, and concentrated. Silica gel chromatography provided a lightyellow oil (2.1 g, 86%), (m/z [M+H]=385.2).

t-Butyl(1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-formylpyridazin-3-yl)carbamate

t-Butyl(1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-vinylpyridazin-3-yl)carbamate(3.4 g, 8.84 mmol) was added as a dioxane (100 mL) solution to a mixtureof sodium periodate (10.8 g, 50.5 mmol) and 4% osmium tetraoxidesolution (6.5 mL) in H₂O (30 mL) at 0° C. The reaction was stirred for 2h. The reaction mixture was filtered through a pad of celite and washedwith EtOAc. The organic layer was washed with satd. aq. NaHCO₃, brineand dried over sodium sulfate, filtered, and concentrated. Silica gelchromatography provided a colorless oil (1.4 g, 41%), (m/z [M+H]=387.2).

Methyl-3-(6-(tert-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)isoxazole-5-carboxylate

To t-butyl(1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-formylpyridazin-3-yl)carbamate(1.4 g, 3.6 mmol) in ethanol (10 mL) and water (2 mL) was addedhydroxylamine hydrochloride (0.27 g, 3.8 mmol) followed by sodiumacetate (0.32 g, 3.8 mmol) and stirred at 24° C. for 30 min. The crudereaction mixture was concentrated and diluted with EtOAc. The organiclayer was washed with satd. aq. NaHCO₃ and brine, then dried over sodiumsulfate, filtered, and concentrated. The crude mixture was then dilutedin THF (2 mL) and pyridine (57 mg, 0.72 mmol) then treated with NCS(0.58 g, 4.35 mmol) and heated to 40° C. for 1.5 h. The crude mixturewas then treated with methyl propiolate (0.30 g, 3.56 mmol) and TEA(0.36, 3.56 mmol), and the reaction was stirred for 45 min. The reactionmixture was concentrated and diluted with EtOAc, and then washed withsatd. aq. NaHCO₃ and brine. The organic layer was dried over sodiumsulfate, filtered, concentrated, and purified by reverse phasechromatography to give a white solid (0.53 g, 31%).

3-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)isoxazole-5-carboxamide

Methyl3-(6-(tert-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)isoxazole-5-carboxylate(0.53 g, 1.1 mmol), methanol (5 mL) and concentrated ammonium hydroxide(8 mL) were combined in a microwave reactor and heated to 100° C. for 60min. The reaction mixture was then concentrated and diluted with EtOAcand washed with satd. aq. NaHCO₃ and brine. The organic layer was driedover sodium sulfate, filtered, and concentrated. Resultant oil wasdiluted in 10 mL of DCM and TFA (6 mL) was added and the reaction wasstirred for 35 min. The reaction mixture was then concentrated andpurified by reverse phase chromatography to give the title compound as awhite solid (144 mg, 36%), (m/z [M+H]=369.1).

EXAMPLE 32 Preparation of2-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazole-5-carboxamide

Ethyl2-(6-(tert-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)thiazole-5-carboxylate

tert-butyl6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(500 mg, 1.27 mmol), ethyl thiazole-5-carboxylate (300 mg, 1.91 mmol),Pd(OAc)₂ (86 mg, 0.13 mmol), JohnPhos (92 mg, 0.26 mmol) and Cs₂CO₃ (827mg, 2.54 mmol) in toluene (10 mL) were combined and heated in amicrowave reactor for 30 min at 145° C. The reaction mixture wasfiltered through a celite plug and the filtrate was concentrated. Theresulting residue was purified on silica gel using a mixture of ethylacetate and hexanes to provide the title compound as yellow oil (162 mg,82% pure, 21%), LRMS (M+H⁺) m/z 514.3.

t-Butyl6-(5-carbamoylthiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

To a solution of ethyl2-(6-(tert-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)thiazole-5-carboxylate(162 mg, 0.32 mmol) in MeOH (8 mL) was purged with NH₃ gas for 5 min.The reaction mixture was sealed and heated in a microwave reactor for 30min at 120° C. The reaction mixture was concentrated and used in nextstep without purification, LRMS (M+H⁺) m/z 484.2.

2-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazole-5-carboxamide

To a crude mixture of t-butyl6-(5-carbamoylthiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(141 mg, crude) in DCM (6 mL) was added TFA (2 mL) at rt. The reactionmixture was further stirred at rt for 2 hr followed by concentration todryness. The crude mixture was purified on RP-HPLC using a mixture ofacetonitrile and H₂O to provide the title compound as a pale yellowsolid (98.5 mg, 99% for 2 steps), LRMS (M+H⁺) m/z 385.2.

EXAMPLE 33 Preparation of5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)isoxazole-3-carboxamide

Ethyl5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)isoxazole-3-carboxylate

To t-butyl6-(1-ethoxyvinyl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(439 mg, 1.02 mmol) in THF (5.0 mL) was added (E)-ethyl2-chloro-2-(hydroxyimino)acetate (465 mg, 3.06 mmol) and TEA (1.4 mL,10.2 mmol). The reaction mixture was stirred at rt for 30 min followedby addition of TFA (5 mL) and then heated to reflux overnight. Themixture was then concentrated and purified by reverse phasechromatography to give 415 mg of the title compound as a colorless oil,LRMS (M+H⁺) m/z 398.3.

5-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)isoxazole-3-carboxamide

To a solution of ethyl5-(6((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)isoxazole-3-carboxylate(200 mg, 0.40 mmol) in THF/MeOH mixture (12 mL, 5:1) was added LiOH (1M, 1.2 mL) at rt. The reaction mixture was stirred overnight andconcentrated. To this crude mixture was added NH₄Cl (60 mg, 1.2 mmol),HBTU (246 mg, 0.65 mmol), DIEA (132 uL, 0.8 mmol), and DMF (5.0 mL). Themixture was stirred at rt overnight, filtered, and purified by reversephase chromatography to provide the title compound as a white solid(23.2 mg, 16%), LRMS (M+H⁺) m/z 369.2.

EXAMPLE 34 Preparation of5-(5-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiophen-2-yl)-2H-1,2,4-triazol-3(4H)-one

t-Butyl6-(5-cyanothiophen-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

t-Butyl6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(900 mg, 2.29 mmol, 1 equiv), 5-cyanothiophen-2-ylboronic acid (390 mg,2.52 mmol, 1.1 equiv), (dppf)PdCl₂ (164 mg, 0.23 mmol, 0.1 equiv),nitrogen-sparged dioxane (6.0 mL) and aq. 2 N K₂CO₃ (2.3 mL) werecombined and heated in a microwave reactor for 30 min at 140° C. Thereaction mixture was filtered through a Celite plug and the filtrate wasconcentrated. The resulting residue was purified on silica gel using amixture of ethyl acetate and hexanes to provide the title compound as ayellow oil (340 mg, 32%), LRMS (M+H⁺) m/z 466.3.

tert-butyl(1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)thiophen-2-yl)pyridazin-3-yl)carbamate

To a solution of tert-butyl6-(5-cyanothiophen-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(340 mg, 0.73 mmol, 1 equiv) in MeOH (10 mL) was added sodium methoxide(0.59 g, 1.1 mmol, 1.5 equiv). The reaction mixture was stirred at rtovernight followed by addition of hydrazine (0.5 mL). The mixture wasthen heated to reflux for 2 h and concentrated to dryness. The crudemixture was partitioned between EtOAc and water. The organic layer waswashed with brine, dried over Na₂SO₄, filtered, and concentrated. Thecrude product was dissolved in dioxane (3 mL), combined with CU (137 mg,1.46 mmol, 2 equiv), and heated for 4 h at 100° C. The mixture wascooled, filtered, and purified by reverse phase chromatography to givethe title compound as a yellow solid (86 mg, 23% over 3 steps), LRMS(M+H⁺) m/z 524.3.

5-(5-(6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiophen-2-yl)-2H-1,2,4-triazol-3(4H)-one

To tert-butyl(1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)thiophen-2-yl)pyridazin-3-yl)carbamate(86 mg, 0.16 mmol) in DCM (6 mL) was added TFA (2 mL) at rt. Thereaction mixture was stirred at rt for 2 hr followed by concentration todryness. The crude mixture was purified by reverse phase chromatographyto provide the title compound as a pale yellow solid (73.6 mg,quantitative). LRMS (M+H⁺) m/z 424.2.

EXAMPLE 35 Preparation of4-fluoro-3-(6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-N-methylbenzamide

1-(3-Fluoropyridin-2-yl)-3-methylenecyclobutanecarbonitrile

To a solution of 3-methylenecyclobutanecarbonitrile (150 g, 1.61 mol, 1equiv) and 2-chloro-3-fluoropyridine (212 g, 1.61 mmol, 1 equiv) intoluene (1 L) was added NaHMDS (2 M in THF, 885 mL, 1.1 equiv) dropwiseat 0-10° C. Upon completion of addition, the reaction mixture was warmedto rt, stirred overnight, and quenched with NH₄C_((sat.)) solution. Theorganic layer was washed with water (500 mL×2) and brine (500 mL), driedover Na₂SO₄, filtered, and concentrated to give a crude title compound(272 g, 90%), which was used in the next step without furtherpurification, LRMS (M+H⁺) m/z 189.1.

1-(3-Fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile

To a mixture of1-(3-fluoropyridin-2-yl)-3-methylenecyclobutanecarbonitrile (272 g, 1.45mol) and RuCl₃.H₂O (9.0 g, 0.044 mol) in DCM (1 L), acetonitrile (1 L),and water (1.5 L) was added solid NaIO₄ (1235 g, 5.8 mol) portionwise at10-30° C. Upon completion of the addition, the reaction was stirred 1 hat 15° C. and overnight at rt. The solid precipitate was filtered offand washed with DCM (1 L×2). The organic layer was washed with water(500 mL×2) and brine (500 mL), dried over Na₂SO₄, and concentrated toprovide the title compound as a crude dark solid (238 g, 86.3%), LRMS(M+H⁺) m/z 191.1.

1-(3-Fluoropyridin-2-yl)-3-hydroxycyclobutanecarbonitrile

To a solution of 1-(3-fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile(231 g, 1.22 mol) in a mixture of DCM (2 L) and MeOH (200 mL) was addedNaBH₄ portion-wise at −78° C. The reaction mixture was stirred 1 h at−78° C. and then quenched with a mixture of methanol and water (1/1).The organic layer was washed with water (500 mL×3), dried over Na₂SO₄,and concentrated. The residue was purified on silica gel (50% EtOAc inHexanes) to provide the title compound as an amber oil (185.8 g, 77.5%),LRMS (M+H⁺) m/z 193.2.

trans-3-Fluoro-1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile

To a solution of1-(3-fluoropyridin-2-yl)-3-hydroxycyclobutanecarbonitrile (185 g, 0.96mol) in DCM (1 L) was added DAST portion-wise at 0-10° C. Upon thecompletion of addition, the reaction was refluxed for 6 h. The reactionwas cooled to rt and poured onto sat. NaHCO₃ solution. The mixture wasseparated and the organic layer was washed with water, dried overNa₂SO₄, and concentrated. The residue was purified on silica gel (100%DCM) to provide the title compound as a brown oil (116 g, 62%) with atrans/cis ratio of 8:1 as determined by ¹H NMR. The above brown oil (107g) was dissolved in a mixture of toluene (110 mL) and hexanes (330 mL)at 70° C. The solution was cooled to 0° C. and stirred at 0° C.overnight. The precipitate was filtered and washed with hexanes toprovide a single trans-isomer white solid (87.3 g, 81.6%), LRMS (M+H⁺)m/z 195.1.

trans-3-Fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine

A mixture oftrans-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile (71 g,0.37 mol) and Raney nickel (˜7 g) in 7N ammonia in methanol (700 mL) wascharged with hydrogen (60 psi) for 2 days. The reaction was filteredthrough a celite pad and washed with methanol. The filtrate wasconcentrated under high vacuum to provide the title compound as a lightgreen oil (70 g, 98%), LRMS (M+H⁺) m/z 199.2.

t-Butyl6-chloropyridazin-3-yl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

3-Chloro-6-fluoropyridazine (10.11 g, 76.30 mmol, 1 equiv),trans-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (15.10 g,76.30 mmol, 4:1 trans/cis ratio), and K₂CO₃ (29.27 g, 304.9 mmol) inCH₃CN (20 mL) were refluxed overnight. Upon cooling, water was addedinto the mixture. The precipitate was collected and dried to give 9.2 g(39%) of desired product with ratio of trans:cis greater than 20:1. Tothis solid (9.2 g) and DMAP (353 mg, 2.9 mmol) in THF (100 mL) was added(Boc)₂O (12.8 g, 58.7 mmol). The mixture was then refluxed for 2 h,cooled, and concentrated. The residue was purified on silica gel toprovide the title compound as a white solid (9 g, 75%), LRMS (M+H⁺) m/z411.2.

Methyl3-(6-(t-butoxycarbonyl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-fluorobenzoate

To t-butyl6-chloropyridazin-3-yl((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(30.3 g, 73.9 mmol, 1 equiv), 2-fluoro-5-(methoxycarbonyl)phenylboronicacid (16.1 g, 81.3 mmol, 1.1 equiv), (dppf)PdCl₂ (6.0 g, 7.39 mmol, 0.1equiv), K₂CO₃ (40.8 g, 296 mmol, 4 equiv) were added dioxane (160 mL)and water (40 mL). The mixture was heated 2 h at 80° C., cooled anddiluted with EtOAc. The organic layer was washed with brine, dried overNa₂SO₄, filtered, and concentrated. The residue was purified on silicagel to provide the title compound as pale orange solid (29.4 g, 75%),LRMS (M+H⁺) m/z 529.2.

3-(6-(t-butoxycarbonyl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-fluorobenzoicacid

To a 500 mL round bottom flask was added methyl3-(6-(t-butoxycarbonyl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-fluorobenzoate(29.4 g, 55.7 mmol, 1 equiv), THF (200 mL), MeOH (100 mL), and NaOH(74.2 mL of a 3N aqueous solution, 222 mmol). The mixture was heated 30min at 60° C., cooled, acidified to pH 3 with NaHSO₄ (1N), andconcentrated. The residue was partitioned between EtOAc and water. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated to provide the title compound as a pale orange solid (29 g,crude), LRMS (M+H⁺) m/z 515.2.

t-Butyl((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(2-fluoro-5-(methylcarbamoyl)phenyl)pyridazin-3-yl)carbamate

To3-(6-(t-butoxycarbonyl(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-fluorobenzoicacid (29 g, 55.7 mmol, 1 equiv) in DCM (200 mL) was added oxalylchloride (19.4 mL, 222 mmol, 4 equiv). The reaction was stirred for 1 h,concentrated, and azeotroped twice with toluene. The crude product wasthen dissolved in DCM and cooled to 0° C. To this mixture was addedNH₂Me (2 M/THF, 278 mL, 556.8 mmol). The mixture was warmed to rt andstirred at rt for 30 min. The solid was filtered off and the filtratewas concentrated. The crude product was purified on silica gel toprovide the title compound as pale yellow solid (28.1 g, 96%), LRMS(M+H⁺) m/z 528.2.

4-fluoro-3-(6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-N-methylbenzamide

Totert-butyl((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(2-fluoro-5-(methylcarbamoyl)phenyl)pyridazin-3-yl)carbamate(28.1 g, 53.3 mmol) in DCM (100 mL) was added TFA (40 mL, 533 mmol, 10equiv) at rt. The reaction mixture was further stirred at rt for 2 hfollowed by concentration to dryness. The residue was partitionedbetween EtOAc and NaHCO₃. The pH was further adjusted to pH 9 with NaOH(1 N). The organic layer was washed with brine, dried over Na₂SO₄,filtered, and concentrated to give 25.2 g of a pale yellow solid. Thesolid was dissolved in EtOH (80 mL), warmed to 66° C. and diluted withwater (80 mL) at 66° C. The mixture was slowly cooled to rt withstirring. The precipitate was filtered, washed with water, and dried toprovide the title compound as a white solid (21.2 g, 93%), LRMS (M+H⁺)m/z 428.2.

EXAMPLE 36 Preparation of6-(5-(1H-pyrazol-3-yl)thiazol-2-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine

t-Butyl6-(5-bromothiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate

To a 100 mL round bottom flask was added t-butyl(1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(thiazol-2-yl)pyridazin-3-yl)carbamate(2.0 g, 4.6 mmol), NBS (1.6 g, 9.1 mmol), and DMF (20 mL). The reactionwas heated to 100° C. and stirred overnight. The reaction mixture wasthen was poured into ethyl acetate (200 mL), washed with water (100 mL),dried over Na₂SO₄, filtered, concentrated, and purified by silica gelchromatography (EtOAc/hex) to afford 1.8 g of t-butyl6-(5-bromothiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.

6-(5-(1H-pyrazol-3-yl)thiazol-2-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine

To a microwave vial was added t-butyl6-(5-bromothiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate(100 mg, 0.19 mmol), 1H-pyrazol-5-ylboronic acid (32 mg, 0.29 mmol),(dppf)PdCl₂ (16 mg, 0.02 mmol), dioxane (2 mL), and K₂CO₃ (0.2 mL of a2M aqueous solution, 38 mmol). The mixture was heated to 140° C. in amicrowave reactor and stirred for 20 min. The reaction mixture was thenpoured into ethyl acetate (50 mL), washed with water (20 mL), dried overNa₂SO₄, filtered, concentrated, and purified by silica gelchromatography (EtOAc/hex) to afford 38 mg of t-butyl6-(5-(1H-pyrazol-3-yl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.This compound was dissolved in CH₂Cl₂ (5 mL) and TFA (1 mL). Thereaction was stirred for 30 min at rt, concentrated, and then purifiedusing reverse phase chromatography to give 15 mg of6-(5-(1H-pyrazol-3-yl)thiazol-2-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine,(M+H=408.3).

EXAMPLE 37 Preparation of6-(6-((trans-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxamide

2-Bromo-1-(6-chloropyridazin-3-yl)ethanone

To a stirring solution of dioxane (100 mL, degassed) was added3,6-dichloropyridazine (5.0 g, 34 mmol), Cl₂Pd(PPh₃)₂ (2.4 g, 3.4 mmol),and tributyl(1ethoxyvinyl)tin (18.2 g, 50 mmol). The reaction was heatedto 100° C. and stirred for 1 h. The reaction was then concentrated,followed by the addition of EtOAc (100 mL) and potassium fluoride (50 mLof a saturated aqueous solution). The mixture was stirred for 30 min andthen filtered through a pad of Celite. The filtrate was concentrated andthen dissolved in THF (80 mL) and water (80 mL). NBS (18.1 g, 102 mmol)was then added, and the reaction was stirred for 20 min at rt. Thereaction mixture was poured into ethyl acetate (200 mL), washed twicewith brine (50 mL), dried over Na₂SO₄, filtered, concentrated, andpurified by silica gel chromatography to afford 4.2 g of2-bromo-1-(6-chloropyridazin-3-yl)ethanone.

Ethyl 6-(6-chloropyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxylate

To a 20 dram vial was added 2-bromo-1-(6-chloropyridazin-3-yl)ethanone(4.2 g, 18 mmol), ethyl-2-aminothiazole-4-carboxylate (3.1 g, 18 mmol),and methylethylketone (40 mL). The mixture was heated to 90° C. andstirred overnight. The reaction was then concentrated and purified bysilica gel chromatography (EtOAc/hex) to afford 1.0 g of ethyl6-(6-chloropyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxylate as ayellow solid.

Ethyl 6-(6-fluoropyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxylate

To a 20 dram vial was added ethyl6-(6-chloropyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxylate (1.0 g,3.2 mmol), 1,8-bis(dimethylamino)naphthalene (1.4 g, 6.4 mmol), andEt₃N.3HF (30 mL). The reaction was heated in a microwave to 140° C. andstirred for 1.5 h. The reaction mixture was poured into ethyl acetate(100 mL), washed with water (50 mL), dried over Na₂SO₄, filtered,concentrated, and purified by silica gel chromatography to afford 760 mgof ethyl 6-(6-fluoropyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxylateas a yellow solid.

Ethyl6-(6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxylate

Ethyl 6-(6-fluoropyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxylate (65mg, 0.2 mmol),(trans-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (56 mg,0.29 mmol), DIPEA (114 μL, 0.66 mmol), and NMP (3 mL). The reaction washeated to 165° C. and stirred for 2 h. The reaction was then purifieddirectly using reverse phase chromatography to give 15 mg of ethyl6-(6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxylate.

6-(6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxamide

To a solution of ethyl6-(6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxylate(20 mg, 0.05 mmol) in dioxane (0.5 mL) was added LiOH (1 M, 0.15 mL,0.15 mmol). The reaction mixture was stirred at rt for 1 h and thenconcentrated. To this crude mixture was added NH₄Cl (28 mg, 0.5 mmol),HATU (28 mg, 0.075 mmol), HOAt (10 mg, 0.075 mmol), DIEA (19 mg, 0.15mmol), and DMF (1 mL). The mixture was stirred at 50° C. for 30 min andthen was purified directly by reverse phase chromatography to provide 2mg of6-(6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxamideas a white solid, (M+H=442.1).

EXAMPLE 38 Preparation of4-Fluoro-3-(6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamideand4-fluoro-3-(6-(((cis)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamide

To a solution of4-fluoro-3-(6((3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzonitrile(482 mg, 1.22 mmol, 95:5 cis/trans ratio) in DMSO (3 mL) was addedpotassium carbonate (673 mg, 4.88 mmol). The mixture was cooled to 0° C.and hydrogen peroxide (0.6 mL) was slowly added. The reaction was warmedto rt and stirred for 2 h. The reaction was diluted with EtOAc (75 mL)and water (50 mL), and the organic layer was washed three times withbrine (50 mL). The organic layer was then dried over Na₂SO₄, filtered,concentrated, and purified by reverse phase chromatography to afford 470mg of4-fluoro-3-(6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamideand 6 mg of4-fluoro-3-(6-(((cis)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamideas white solids (M+H=414.3).

EXAMPLE 39 Preparation and Assay of Fast Skeletal Myofibrils

Preparation of Fast Skeletal Myofibrils.

Rabbit skeletal myofibrils were prepared based upon the method ofHerrmann et al. (Biochem. 32(28):7255-7263 (1993). Myofibrils wereprepared from rabbit psoas muscle purchased from Pel-Freez Biologicals(Arkansas) within 2 days of ordering, stored on ice. Minced muscle washomogenized in 10 volumes of ice-cold “standard” buffer (50 mM Tris, pH7.4, 0.1 M potassium acetate, 5 mM KCl, 2 mM DTT, 0.2 mM PMSF, 10 μMleupeptin, 5 μM pepstatin, and 0.5 mM sodium azide) containing 5 mM EDTAand 0.5% Triton X-100 using an Omni-Macro homogenizer. Myofibrils wererecovered by low speed centrifugation (3000 rpm for 10 minutes) andwashed 2 times in the Triton X-100 containing buffer to ensure removalof cellular membrane. Following the Triton washes, myofibrils werewashed 3 times in “standard” buffer containing 2 mM magnesium acetate. Afinal wash in assay buffer (12 mM PIPES, pH 6.8, 60 mM KCl, 1 mM DTT)was performed and brought to 10% sucrose for flash freezing in liquidnitrogen and storage at −80° C.

Activation of Fast Skeletal Myofibrils.

Fast fiber activators were identified by measuring the enzymaticactivity of muscle myofibril preparations using the proprietary PUMA™(see, e.g., U.S. Pat. Nos. 6,410,254, 6,743,599, 7,202,051, and7,378,254) assay system. Myofibril preparations consisted of rabbitskeletal muscle (approximately 90% fast fibers) that had beenmechanically homogenized and washed with a detergent (triton X-100) toremove cellular membranes. This preparation retained all of thesarcomeric components in a native conformation and the enzymaticactivity was still regulated by calcium. Compounds were tested using amyofibril suspension and a level of calcium sufficient to increaseenzymatic activity of the myofibrils to 25% of their maximal rate(termed pCa25). Enzymatic activity was tracked via a pyruvate kinase andlactate dehydrogenase-coupled enzyme system. This assay regeneratesmyosin-produced ADP into ATP by oxidizing NADH, producing an absorbancechange at 340 nm. The buffering system was 12 mM Pipes, 2 mM MgCl₂, 1 mMDTT at pH 6.8 (PM12 buffer). Data was reported as AC1.4, which is theconcentration at which the compound increased the enzymatic activity by40%. The results are summarized in Table 2 below.

EXAMPLE 40 Preparation and Assay of Sarcomeric Proteins from SkeletalMuscle

Powder Preparation

1. Volumes are given per about 1000 g of the minced muscle.2. Pre-cut and boil cheesecloth for 10 min in water. Drain and dry.3. Mince chicken breast in a prechilled meat grinder.4. Extract with stirring in 2 L of 0.1 M KCl, 0.15 M K-phosphate, pH 6.5for 10 min at 4° C. Spin 5000 rpm, 10 min, 4° C. in JLA. Collect thepellet.5. Extract pellets with stirring with 2 L of 0.05 M NaHCO₃ for 5 min.Spin 5000 rpm, 10 min, 4° C. in JLA. Collect the pellet. Repeat theextraction once more.6. Extract the filtered residue with 2 L of 1 mM EDTA, pH 7.0 for 10 minwith stirring.7. Extract with 2 L of H₂O for 5 min with stirring. Spin 10000 rpm, 15min, 4° C. in JLA. Carefully collect the pellet, part of which will beloose and gelatinous.8. Extract 5 times with acetone (2 L of acetone for 10 min each withstirring). Squeeze through cheesecloth gently. All acetone extractionsare performed at room temperature. Acetone should be prechilled to 4° C.9. Drying: Place the filtered residue spread on a cheesecloth in a largeglass tray and leave in a hood overnight. When the residue is dry, putin a wide mouth plastic bottle and store at 20° C.

Alternate Powder Preparation

(See Zot & Potter (1981) Prep. Biochem. 11(4) pp. 381-395)1. Dissect left ventricles of the cardiac muscle. Remove as much of thepericardial tissue and fat as possible. Grind in a prechilled meatgrinder. Weigh.2. Prepare 5 volumes of Extract buffer (see below). Homogenize the meatin a blender, 4 times 15 sec on blend with 15 secs in between. Do thiswith 1 volume (weight/volume) of buffer taken from the 5 volumes alreadyprepared. Add the homogenate back to the extract buffer and stir untilwell mixed (5 minutes).3. Filter through one layer of cheesecloth in large polypropylenestrainer. Resuspend back into 5 volumes of extract buffer as above.4. Repeat Step 3 four more times. At the end, do not resuspend inextraction buffer but proceed to Step 5. The pellets should be yellowwhite.5. Resuspend in 3 volumes (according to original weight) of 95% coldethanol. Stir for 5 min and squeeze through cheesecloth as above, repeattwo more times.6. Weigh squeezed residue and then resuspend in 3 volumes (newweight/volume) of cold diethyl ether.7. Repeat Step 6 a total of three times.8. Leave overnight in a single layer on a cheesecloth in a glass tray.9. When dry, collect the powder, weigh and store in a wide-mouth jar at4° C.EXTRACT BUFFER: 50 mM KCl, 5 mM Tris pH 8.0 Prepare as 50 timesconcentrate. For 2 L: 250 mM Tris pH 8.0. Tris Base (121.14 g/mol, 60.6g), pH to 8.0 with conc. HCl, then add 2.5 M KCl (74.55 g/mol, 372 g).

Actin Preparation

1. Extract powder (as described above) with 20 ml buffer A (see below,add BME and ATP just prior to use in each of the following steps) pergram of powder (200 ml per 10 g). Use a large 4 L beaker for 150 g ofpowder. Mix vigorously to dissolve powder. Stir at 4° C. for 30 min.2. Separate extract from the hydrated powder by squeezing throughseveral layers of cheesecloth. Cheesecloth should be pre-sterilized bymicrowaving damp for 1-2 min.3. Re-extract the residue with the same volume of buffer A and combineextracts.4. Spin in JLA10 rotor(s) for 1 hr at 10K rpm (4° C.). Collectsupernatant through 2 layers of cheesecloth.5. Add ATP to 0.2 mM and MgCl₂ to 50 mM. Stir on stir plate at 4° C. for60 minutes to allow actin to polymerize/form para-crystals.6. Slowly add solid KCl to 0.6 M (45 g/l). Stir at 4° C. for 30 min.7. Spin in JLA10 rotor(s) at 10K rpm for 1 hr.8. Depolymerization: Quickly rinse surface of pellets with buffer A anddispose of wash. Soften the pellets by pre-incubation on ice with smallamount of buffer A in each tube (use less than half of finalresuspension volume total in all tubes). Resuspend by hand first withcell scraper and combine pellets. Wash tubes with extra buffer using a25 ml pipette and motorized pipettor, aggressively removing actin fromsides of tubes. Homogenize in large dounce in cold buffer A on ice. Use3 ml per gram of powder originally extracted.9. Dialyze against buffer A with 4 changes over 48 hour period.10. Collect dialyzed actin and spin in the 45Ti rotor at 40K rpm for 1.5hr (4° C.).11. Collect supernatant (G-Actin). Save a sample for gel analysis anddetermination of protein concentration.12. To polymerize G-actin for storage, add KCl to 50 mM (from 3 Mstock), MgCl₂ to 1 mM, and NaN₃ to 0.02% (from 10% stock). Store at 4°C. Do not freeze.Buffer A: 2 mM tris/HCl, 0.2 mM CaCl₂, 0.5 mM (36 μl/L)2-mercaptoethanol, 0.2 mM Na₂ ATP (added fresh), and 0.005% Na-azide; pH8.0.

Purification of Skeletal Muscle Myosin

(See Margossian, S. S, and Lowey, S. (1982) Methods Enzymol. 85, 55-123;and Goldmann, W. H. and Geeves, M. A. (1991) Anal. Biochem. 192, 55-58)Solution A: 0.3 M KCl, 0.15 M potassium phosphate, 0.02 M EDTA, 0.005 MMgCl₂, 0.001 M ATP, pH 6.5.Solution B: 1 M KCl, 0.025 M EDTA, 0.06 M potassium phosphate, pH 6.5.Solution C, 0.6 M KCl, 0.025 M potassium phosphate, pH 6.5.Solution D: 0.6 M KCl, 0.05 M potassium phosphate, pH 6.5.Solution E: 0.15 M potassium phosphate, 0.01 M EDTA, pH 7.5.Solution F: 0.04 M KCl, 0.01 M potassium phosphate, 0.001 M DTT, pH 6.5.Solution G: 3 M KCl, 0.01 M potassium phosphate, pH 6.5.All procedures are carried out at 4° C.1. Obtain approx. 1000 g skeletal muscle, such as rabbit skeletalmuscle.2. Grind twice; extract with 2 L solution A for 15 min while stirring;add 4 L cold H₂O, filter through gauze; dilute with cold H₂O to ionicstrength of 0.04, (about 10-fold); let settle for 3 h; collectprecipitate at 7,000 rpm in GSA rotor for 15 min.3. Disperse pellet in 220 ml solution B; dialyze overnight against 6 Lsolution C; slowly add ˜400 ml equal volume cold distilled H₂O; stir for30 min; centrifuge at 10,000 rpm for 10 min in GSA rotor.4. Centrifuge supernatant at 19,000 rpm for 1 h.5. Dilute supernatant to ionic strength of 0.04 (˜8-fold); let myosinsettle overnight; collect about 5-6 L fluffy myosin precipitate bycentrifuging at 10,000 rpm for 10 min in GSA rotor.6. Resuspend pellet in minimal volume of solution G; dialyze overnightagainst 2 L solution D; centrifuge at 19,000 rpm for 2 h, in cellulosenitrate tubes; puncture tubes and separate myosin from fat and insolublepellet.7. Dilute supernatant to 5-10 mg/ml and dialyze against solution Eextensively, load onto DEAE-sephadex column.8. Pre-equilibrate with solution E; apply 500-600 g myosin at 30 ml/h;wash with 350 ml solution E; elute with linear gradient of 0-0.5 M KClin solution E (2×1 liter); collect 10 ml fractions; pool myosinfractions (>0.1 M KCl); concentrate by overnight dialysis againstsolution F; centrifuge at 25,000 rpm for 30 min; store as above.9. The myosin is then cut with chymotrypsin or papain in the presence ofEDTA to generate the S1 fragment which is soluble at the low saltconditions optimal for ATPase activity (Margossian, supra).

Preparation and Assay

Myosin is prepared by precipitation from salt extracts of rabbit psoasmuscle, and a soluble S1 fraction is prepared by digestion withchymotrypsin (Margossian and Lowey, 1982).

Actin is purified by first preparing an ether powder of cardiac muscle(Zot H G and Potter J D. (1981) Preparative Biochemistry 11:381-395) asdescribed above. Subsequently, actin is cycled between the filamentousand soluble state through rounds of centrifugation and dialysis (SpudichJ A and Watt S. (1971) J. Biol. Chem. 246:4866-4871).

Tropomyosin is extracted from the ether powder and separated from theother proteins based on pH dependent precipitations followed bysuccessive ammonium sulfate cuts at 53% and 65% (Smillie L B. (1981)Methods Enzymol 85 Pt B:234-41). The troponins are isolated as an intactcomplex of TnC, TnT, and TnI. Ether powder is extracted in a high saltbuffer. Successive ammonium sulfate cuts of 30% and 45% are done; theprecipitate is solubilized by dialysis into a low salt buffer and thenfurther purified on a DEAE Toyopearl column with a 25-350 mM KClgradient. There is no measurable ATPase in any of the components exceptfor myosin which naturally had a very low basal ATPase in the absence ofactin.

Prior to screening, the actin, tropomyosin, and troponin complex aremixed together in the desired ratio (e.g., 7:1:1) to achieve maximalcalcium regulation of the actin filament. The screen is conducted at aconcentration that gives 25% activation. This calcium concentration isin the physiological range during muscle contraction.

To measure the generation of ADP during the reaction, a pyruvatekinase/lactate dehydrogenase/NADH coupled enzyme system (PK/LDH) isadded to the actin. The myosin is kept separately, and added to theregulated thin filaments to initiate the reaction. Oxidation of NADH ismonitored in real time, so that kinetic curves are obtained. Compoundsare dissolved in DMSO and spotted onto the bottoms of 384 well plates at10 to 40 μg/ml final concentration.

Using procedures similar to those described herein, utilizing reagentsand intermediates commercially available (e.g., Sigma-Aldrich, St.Louis, Mo.) or readily synthesized by one of skill in the art, thecompounds in Table 2 were synthesized, characterized and tested. AC1.4values were determined according to the procedure described in Example39, and the reported median AC1.4 values are as follows: A=<1 uM; B=1-10uM; C=10-20 uM; D=>20 uM.

TABLE 2 m/z Mean Compound Structure (M + H) AC1.43-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)benzamide

365.2 A 4-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)benzamide

365.1 B 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)pyridine-3-carbonitrile

348.1 B methyl 5-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)pyridine-3-carboxylate

381.1 B 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)pyridine-3-carboxamide

366.1 B [2-(4-fluorophenyl)-2- methylpropyl](6-pyrazol-4-ylpyridazin-3-yl)amine

312.1 B [2-(4-fluorophenyl)-2- methylpropyl](6-prop-2-enylpyridazin-3-yl)amine

281.6 B [6-((1E)prop-1-enyl)pyridazin-3- yl][2-(4-fluorophenyl)-2-methylpropyl]amine

286.1 B 3-(6-{[(2S)-2-(4- fluorophenyl)propyl]amino}pyridazin-3-yl)benzamide

351.0 B 3-(6-{[(2R)-2-(4- fluorophenyl)propyl]amino}pyridazin-3-yl)benzamide

351.0 B 3-(6-{[2-(4- chlorophenyl)ethyl]amino}pyridazin- 3-yl)benzamide

353.1 D 3-(6-{[2-(3- chlorophenyl)ethyl]amino}pyridazin- 3-yl)benzamide

353.1 B 3-(6-{[2-(2- chlorophenyl)ethyl]amino}pyridazin- 3-yl)benzamide

353.1 B 3-(6-{[2-(4- methylphenyl)ethyl]amino}pyridazin- 3-yl)benzamide

333.2 C 3-(6-{[2-(4- fluorophenyl)ethyl]amino}pyridazin- 3-yl)benzamide

337.1 D 3-(6-{[2-(4- methoxyphenyl)ethyl]amino}pyridazin- 3-yl)benzamide

349.1 D (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)methan-1-ol

276.1 D methyl 6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazine-3- carboxylate

304.2 C 3-(6-{[2-(2,4- dichlorophenyl)ethyl]amino}pyridazin-3-yl)benzenecarbonitrile

369.0 D 3-(6-{[2-(2,4- dichlorophenyl)ethyl]amino}pyridazin-3-yl)benzamide

387.0 C 3-(6-{[2-(3,4- dichlorophenyl)ethyl]amino}pyridazin-3-yl)benzamide

387.0 C 3-(6-{[2-(2,4- difluorophenyl)ethyl]amino}pyridazin-3-yl)benzamide

355.1 D 3-(6-{[2-(3,4- difluorophenyl)ethyl]amino}pyridazin-3-yl)benzamide

355.1 C 3-(6-{[2-(3,5- difluorophenyl)ethyl]amino}pyridazin-3-yl)benzamide

355.1 D 3-{6-[(2-(4- pyridyl)ethyl)amino]pyridazin-3- yl}benzamide

320.1 D 3-{6-[(2-(3- pyridyl)ethyl)amino]pyridazin-3- yl}benzamide

320.1 D 3-{6-[(2-(2- pyridyl)ethyl)amino]pyridazin-3- yl}benzamide

320.1 D 3-{6-[(2- phenylethyl)amino]pyridazin-3- yl}benzamide

319.1 D 3-{6-[(3- methylbutyl)amino]pyridazin-3- yl}benzamide

319.1 D 3-{6-[(2- phenylpropyl)amino]pyridazin-3- yl}benzamide

333.1 B 3-(6-{[(4- fluorophenyl)ethyl]amino}pyridazin- 3-yl)benzamide

337.1 C 3-{6- [(phenylethyl)amino]pyridazin-3- yl}benzamide

319.1 D 3-{6-[(3,3- dimethylbutyl)amino]pyridazin-3- yljbenzamide

299.2 D 3-{6-[(2-pyrazin-2- ylethyl)amino]pyridazin-3- yl}benzamide

321.1 D 3-(6-{[2-(2-chlorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)benzamide

381.1 A 3-(6-{[2-(4-chlorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)benzamide

381.1 B 3-(6-{[2-(2,4-difluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)benzamide

383.1 B 3-[6-({[(4- fluorophenyl)cyclopropyl]meth-yl}amino)pyridazin-3-yl]benzamide

362.2 A (6-(1H-indazol-6-yl)pyridazin-3- yl)[2-(4-fluorophenyl)-2-methylpropyl]amine

362.1 A 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)benzenecarbonitrile

347.1 B (6-(1H-indazol-5-yl)pyridazin-3- yl)[2-(4-fluorophenyl)-2-methylpropyl]amine

362.2 A 3-(6-{[2-(2-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)benzamide

365.1 A (6-(1H-indazol-4-yl)pyridazin-3- yl)[2-(4-fluorophenyl)-2-methylpropyl]amine

362.1 A 5-[6-({[(4- fluorophenyl)cyclopropyl]meth-yl}amino)pyridazin-3-yl]pyridine-3- carboxamide

364.1 B 5-[6-({[(4- fluorophenyl)cyclopropyl]meth-yl}amino)pyridazin-3-yl]pyridine-3- carbonitrile

346.1 B 6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazine-3-carbonitrile

271.1 D 6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazine-3-carboxamide

289.1 C 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-3-hydrobenzimidazol-2-one

378.1 A 3-(6-{[2-(3-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)benzamide

365.1 A (6-(1H-1,2,3,4-tetraazol-5- yl)pyridazin-3-yl)[2-(4-fluorophenyl)-2- methylpropyl]amine

314.1 D 5-(6-{[2-(2-chlorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)pyridine-3-carboxamide

382.1 B 5-(6-{[2-(2-chlorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)pyridine-3-carbonitrile

364.1 B [(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)methyl](methylsulfonyl)amine

353.1 B N-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)methyl]methoxycarboxamide

333.2 D [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl][2-(4-fluorophenyl)-2- methylpropyl]amine

377.1 A [6-(3-amino(1H-indazol-7- yl))pyridazin-3-yl][2-(4-fluorophenyl)-2- methylpropyl]amine

377.0 B [6-(3-aminobenzo[3,4-d]isoxazol- 5-yl)pyridazin-3-yl][2-(4-fluorophenyl)-2- methylpropyl]amine

378.0 B [6-(3-aminobenzo[d]isoxazol-7- yl)pyridazin-3-yl][2-(4-fluorophenyl)-2- methylpropyl]amine

388.0 B [2-(2-chlorophenyl)-2- methylpropyl](6-(3-pyridyl)pyridazin-3-yl)amine

339.1 B [2-(2-chlorophenyl)-2- methylpropyl](6-pyrimidin-5-ylpyridazin-3-yl)amine

340.1 B 3-[6-({[(2- chlorophenyl)cyclopropyl]methyl}amino)pyridazin-3-yl]benzamide

379.1 A 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-5-methylpyridazin-3- yl)benzenecarbonitrile

361.1 C 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-5-methylpyridazin-3-yl)benzamide

379.1 B 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-4-methylpyridazin-3- yl)benzenecarbonitrile

361.1 B 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-4-methylpyridazin-3-yl)benzamide

379.1 B [3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)phenyl]-N-(2- hydroxyethyl)carboxamide

409.1 B N-(2,3-dihydroxypropyl)[3-(6-{[2- (4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)phenyl]carboxamide

439.1 B 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)phenyl piperidyl ketone

433.2 B 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)phenyl morpholin-4-yl ketone

435.1 B N-(2-aminoethyl)[3-(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)phenyl]carboxamide

408.2 A [3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)phenyl]-N-(2-{[3-(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)phenyl]carbonylamino}ethyl)car-boxamide

755.3 B tert-butyl 4-{[3-(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)phenyl]carbonyl}piperazinecar-boxylate

534.2 B 2-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)benzamide

365.0 B 5-[6-({[(4- fluorophenyl)cyclopropyl]meth-yl}amino)pyridazin-3-yl]-3- hydrobenzimidazol-2-one

376.1 A [2-(4-fluorophenyl)-2- methylpropyl][6-(1-methyl(1H-indazol-6-yl))pyridazin-3-yl]amine

376.2 B 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)phenyl piperazinyl ketone

434.2 B 1-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)carbonyl]pyrrolidine-2- carboxamide

386.1 D ethyl 1-[(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)carbonylamino]cyclopropanecar-boxylate

401.1 D 6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazine-3-carboxylic acid

290.1 D 1-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)carbonylamino]cyclopropanecar- boxylic acid

373.1 D 3-(6-{[2-(2- chlorophenyl)pentyl]amino}pyridazin- 3-yl)benzamide

395.1 B [6-(3-amino-1-methyl(1H-indazol- 5-yl))pyridazin-3-yl][2-(4-fluorophenyl)-2- methylpropyl]amine

391.0 B 3-(6-{[2-(2-fluorophenyl)-4- methoxybutyl]amino}pyridazin-3-yl)benzamide

395.1 D 6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-ylmorpholin-4-yl ketone

359.1 D 6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl4-methylpiperazinyl ketone

372.1 D tert-butyl 4-[(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)carbonyl]piperazinecarboxylate

458.2 D tert-butyl 4-[(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)carbonyl]-3-(hydroxymethyl)piperazinecar- boxylate

488.2 D 1-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)carbonyl]azetidine-2- carboxamide

372.1 D 1-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)carbonyl]piperidine-2- carboxamide

400.1 D 4-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)carbonyl]piperazin-2-one

372.1 D 5-(6-{[2-(2-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-3-hydrobenzimidazol-2-one

378.2 A [6-(3-amino(1H-indazol-6- yl))pyridazin-3-yl][2-(4-fluorophenyl)-2- methylpropyl]amine

377.0 A [6-(3-aminobenzo[d]isoxazol-6- yl)pyridazin-3-yl][2-(4-fluorophenyl)-2- methylpropyl]amine

378.0 A 3-fluoro-5-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)benzamide

383.1 B N-(1-carbamoyl-3-methylbutyl)(6- {[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)carboxamide

402.2 C N-((1S)-1-carbamoyl-2- hydroxyethyl)(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)carboxamide

376.1 D (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-N-(pyrazol-3- ylmethyl)carboxamide

369.1 C 3-(5-cyano-6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)benzamide

390.2 C 6-(3-carbamoylphenyl)-3-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazine-4- carboxamide

408.2 B 5-[6-({2-[2- (hydroxymethyl)phenyl]-2-methylpropyl}amino)pyridazin-3- yl]-3-hydrobenzimidazol-2-one

390.1 B 1-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)carbonyl]piperidine-3- carboxamide

400.1 D (2S,1R)-2-[(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)carbonylamino]cyclopentanecar-boxamide

400.1 D N-(2-carbamoylethyl)(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)carboxamide

360.1 D 4-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)carbonyl]piperazine-2- carboxamide

401.1 D 1-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)carbonyl]pyrrolidine-3- carboxamide

386.1 D 1-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)carbonylamino]cyclopropanecar- boxamide

372.1 D 5-{6-[(2,2- dimethylpropyl)amino]pyridazin-3-yl}-3-hydrobenzimidazol-2-one

298.2 D 3-(6-{[3-(1,3-dioxolan-2-yl)-2-(2-fluorophenyl)propyl]amino}pyridazin- 3-yl)benzamide

423.1 D 6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-ylpiperazinyl ketone

358.0 D 4-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)carbonyl]piperazinecarboxamide

401.0 D 5-{6-[(2-methyl-2- phenylpropyl)amino]pyridazin-3-yl}-3-hydrobenzimidazol-2-one

360.1 A 5-(6-{[2-(4-fluorophenyl)-tert- butyl]amino}pyridazin-3-yl)-3-hydrobenzimidazol-2-one

378.1 D (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yi)-N-pyrazol-5-ylcarboxamide

355.1 D (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-N-(2-oxo(3- piperidyl))carboxamide

386.1 D 4-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)carbonylamino)piperidinecar- boxamide

401.1 D (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-N-[(5-oxopyrrolidin-2- yl)methyl]carboxamide

386.2 C 3-(6-{[2-(2- fluorophenyl)butyl]amino}pyridazin- 3-yl)benzamide

365.1 B (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-N-(2-oxopyrrolidin-3- yl)carboxamide

372.1 C N-{3-[(tert- butoxy)carbonylamino]propyl}[3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)phenyl]carboxamide

522.2 B N-(3-aminopropyl)[3-(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)phenyl]carboxamide

422.2 B (6-benzimidazol-5-ylpyridazin-3- yl)[2-(4-fluorophenyl)-2-methylpropyl]amine

362.2 A [2-(4-fluorophenyl)-2- methylpropyl][6-(2- methylbenzimidazol-5-yl)pyridazin-3-yl]amine

376.2 B [6-(2-aminobenzimidazol-5- yl)pyridazin-3-yl][2-(4-fluorophenyl)-2- methylpropyl]amine

377.2 A [3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)phenyl]-N-methylcarboxamide

379.1 B 3-(6-{[2-(2- oxopyrrolidinyl)propyl]amino}pyrid-azin-3-yl)benzamide

340.1 D 3-(6-{[2-(2- oxopiperidyl)propyl]amino}pyridazin- 3-yl)benzamide

354.1 D N-[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-2-pyridyl]acetamide

380.2 B [2-(4-fluorophenyl)-2- methylpropyl][6-(2-methylbenzoxazol-5-yl)pyridazin- 3-yl]amine

377.2 B [2-(4-fluorophenyl)-2- methylpropyl][6-(2-methylbenzoxazol-6-yl)pyridazin- 3-yl]amine

377.2 B 1-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)carbonyl]piperidine-4- carboxamide

400.2 D N-((1S)-1-carbamoyl-2- phenylethyl)(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)carboxamide

436.1 C N-((1R)-1-carbamoyl-2- phenylethyl)(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)carboxamide

436.1 C N-(carbamoylmethyl)(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)carboxamide

346.1 D N-(1,3-dicarbamoylpropyl)(6-{[2- (4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)carboxamide

417.1 D 3-(6-{[2-(2- fluorophenyl)propyl]amino}pyridazin- 3-yl)benzamide

351.1 B 3-(6-{[2-(3-fluoro(2-pyridyl))-2-methylpropyl]amino}pyridazin-3- yl)benzamide

366.1 B 3-(6-{[2-(5-fluoro(2-pyridyl))-2-methylpropyl]amino}pyridazin-3- yl)benzamide

366.1 C 3-[6-(3,3- dimethylindolinyl)pyridazin-3- yl]benzamide

345.2 D 6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-3-hydrobenzoxazol-2-one

379.2 A 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)phenyl phenyl ketone

426.2 D 4-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)phenyl phenyl ketone

426.2 D [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]{[(4-fluorophenyl)cyclopropyl)meth- yl}amine

375.3 A [2-(4-fluorophenyl)-2- methylpropyl][6-(3-iodo(1H-indazol-5-yl))pyridazin-3-yl]amine

488.0 B [2-(4-fluorophenyl)-2- methylpropyl](6-(4-1,2,5,6-tetrahydropyridyl)pyridazin-3- yl)amine

327.2 B [2-(4-fluorophenyl)-2- methylpropyl](6-pyrazol-3-ylpyridazin-3-yl)amine

312.1 B 1-acetyl-4-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)-1,2,5,6-tetrahydropyridine

369.1 D methyl 4-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)-1,2,5,6-tetrahydropyridine-carboxylate

385.1 C 4-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1-(methylsulfonyl)-1,2,5,6- tetrahydropyridine

405.1 B 4-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1,2,5,6- tetrahydropyridinecarboxamide

370.1 B 3-{6-[(2- piperidylpropyl)amino]pyridazin-3- yl}benzamide

340.1 D [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl](2-piperidylpropyl)amine

352.2 D 3-{6-[(1,2,3,4- tetrahydronaphthylmethyl)amino]py-ridazin-3-yl}benzamide

359.0 B (tert-butoxy)-N-(2-{[5-(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)(1H-indazol-3-yl)]amino}ethyl)carboxamide

520.2 A [2-(4-fluorophenyl)-2- methylpropyl](6-pyrrolo[3,2-b]pyridin-6-ylpyridazin-3-yl)amine

362.2 A [2-(4-fluorophenyl)-2- methylpropyl](6-pyrazolo[5,4-b]pyridin-5-ylpyridazin-3-yl)arnine

363.2 B 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-3-hydrobenzoxazol-2-one

379.2 B [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]{[(2-fluorophenyl)cyclopropyl]meth- yl}amine

375.1 A [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]{[(2-fluorophenyl)cyclobutyl]meth- yl}amine

389.1 A [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl][2,2-difluoro-2-(4-fluorophenyl)ethyl]amine

385.0 B 3-[6-(indan-2-ylamino)pyridazin-3- yl]benzamide

331.0 D 3-{6- [(indanylmethyl)amino]pyridazin-3- yl}benzamide

345.0 B (6-{3-[(2-aminoethyl)amino](1H-indazol-5-yl)}pyridazin-3-yl)[2-(4- fluorophenyl)-2- methylpropyl]amine

420.1 A 1-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)ethan-1-one

288.1 D 4-fluoro-3-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)benzamide

283.1 A 3-{6-[((2S,1R)-2- phenylcyclopropyl)amino]pyridazin-3-yl}benzamide

331.0 D [2-(4-fluorophenyl)-2- methylpropyl][6-(3-methyl(1H-indazol-6-yl))pyridazin-3-yl]amine

376.0 B [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]{[(4-fluorophenyl)cyclobutyl]meth- yl}amine

389.1 A [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]{[(2-fluorophenyl)cyclopentyl]meth- yl}amine

403.1 A [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl][2-methyl-2-(2-methylphenyl)propyl]amine

373.2 A [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]{[(4-fluorophenyl)cyclohexyl]meth- yl}amine

417.2 A [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl][(phenylcyclopropyl)methyl]amine

357.1 A [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl][(phenylcyclobutyl)methyl]amine

371.1 A [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl][(2,2-dimethyl-1-phenylcyclopropyl)methyl]amine

385.2 A 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1H-indazole-3-carbonitrile

387.1 D [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]{[(4-fluorophenyl)cyclopentyl]meth- yl}amine

403.1 A 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1H-indazole-3-carboxamide

405.1 A [4-(2-{[6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]amino}-tert-butyl)phenyl]methan-1-ol

389.2 D {[4-(2-{[6-(3-amino(1H-indazol-5-yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]methyl}dimethylamine

416.2 D [2-(4-fluorophenyl)-2- methylpropyl][6-(3-vinyl(1H-indazol-5-yl))pyridazin-3-yl]amine

388.1 A [6-(3-ethyl(1H-indazol-5- yl))pyridazin-3-yl][2-(4-fluorophenyl)-2- methylpropyl]amine

390.2 B 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1,2,4-oxadiazole-5- carboxamide

357.1 C [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl][2-(3-fluoro(2-pyridyl))-2-methylpropyl]amine

378.1 B [6-(3-amino(1H-indazol-6- yl))pyridazin-3-yl][2-(3-fluoro(2-pyridyl))-2-methylpropyl]amine

378.1 B [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl][2-(5-fluoro(2-pyridyl))-2-methylpropyl]amine

378.1 B [6-(3-amino(1H-indazol-6- yl))pyridazin-3-yl][2-(5-fluoro(2-pyridyl))-2-methylpropyl]amine

378.1 C 1-[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1H-indazol-3-yl]ethane-1,2-diol

422.1 B 2-amino-6-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)-3-hydropyrimidin-4-one

355.1 B N-[6-(2-amino-6- oxohydropyrimidin-4-yl)pyridazin-3-yl](tert-butoxy)-N-[2-(4- fluorophenyl)-2- methylpropyl]carboxamide

455.1 B 6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-3-hydroquinazolin-4-one

390.1 B [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl](2-methyl-2-(1,3-oxazol-2-yl)propyl)amine

350.3 D ethyl 2-fluoro-5-(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)benzoate

412.2 B 2-amino-6-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)-3-hydroquinazolin-4-one

405.1 A 4-(2-{[6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]amino}-tert-butyl)benzenecarbonitrile

384.1 A 4-(2-{[6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]amino}-tert-butyl)benzamide

402.2 D [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]{2-[4-(aminomethyl)phenyl]-2- methylpropyl]amine

388.2 D 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1H-indazole-3-carboxamidine

404.1 B 2-[4-(2-{[6-(3-amino(1H-indazol-5-yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]propan-2-ol

417.2 D [3-(2-{[6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]amino}-tert-butyl)phenyl]methan-1-ol

389.2 B 2-[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1H-indazol-3-yl]propan-2-ol

420.1 B 3-(6-{[2-(3,5-difluoro(2-pyridyl))-2-methylpropyl]amino}pyridazin-3- yl)benzamide

384.0 B [5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1H-indazol-3-yl]methan-1-ol

392.1 A {[3-(2-{[6-(3-amino(1H-indazol-5-yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]methyl}dimethyl- amine

416.3 D 3-(2-{[6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]amino}-tert-butyl)benzenecarbonitrile

384.2 A 3-(2-{[6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]amino}-tert-butyl)benzamide

402.2 D 2-[3-(2-{[6-(3-amino(1H-indazol-5-yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]propan-2-ol

417.2 C [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl][2-(3,5-difluoro(2-pyridyl))-2- methylpropyl]amine

396.0 A [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

390.0 A 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]benzamide

378.2 A N-[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1H-indazol-3-yl]acetamide

419.1 A [6-(3-aminopyrazolo[5,4-b]pyridin- 5-yl)pyridazin-3-yl][2-(4-fluorophenyl)-2- methylpropyl]amine

387.3 A [3-(2-{[6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]amino}-tert-butyl)phenyl]-N- methylcarboxamide

416.2 D [3-(2-{[6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]amino}-tert-butyl)phenyl)-N,N- dimethylcarboxamide

430.2 C [5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)(1H-indazol-3- yl)](methylsulfonyl(amine

455.1 A [2-(2-{[6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]amino}-tert-butyl)phenyl]methan-1-ol

389.1 B [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]{2-[3-(aminomethyl)phenyl]-2- methylpropyl}amine

388.2 C {[(4- fluorophenyl)cyclobutyl]methyl}[6- (2-methoxypyrimidin-5-yl)pyridazin-3-yl]amine

366.1 B 5-[6-({[(4- fluorophenyl)cyclobutyl]meth-yl}amino)pyridazin-3-yl]-3- hydropyrimidin-2-one

352.1 B 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1H-indazole-7-carboxamide

405.1 B [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl][2-(3-methoxyphenyl)-2- methylpropyl]amine

389.1 A [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl][2-methyl-2-(4-methylphenyl)propyl]amine

373.1 A 2-[3-(2-{[6-(3-amino(1H-indazol-5-yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]ethan-1-ol

403.2 B [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]{[(5-fluoro(2-pyridyl))cyclobutyl]methyl}amine

390.0 A 3-[6-({[(5-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]benzamide

378.0 B (tert-butoxy)-N-[6-(2,3-dioxo(1,4-dihydroquinoxalin-6-yl))pyridazin- 3-yl]-N-[2-(4-fluorophenyl)-2-methylpropyl]carboxamide

506.1 D {2-[3-(2-{[6-(3-amino(1H-indazol-5-yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]ethyl}dimethylamine

430.2 D 3-(2-{[6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]amino}-tert-butyl)phenol

375.1 B 6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1,4-dihydroquinoxaline-2,3- dione

406.1 A [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]{2-[2-(methoxymethyl)phenyl]-2- methylpropyl}amine

403.2 C 3-(6-{(tert-butoxy)-N-[2-(3- fluoro(2-pyridyl))-2-methylpropyl]carbonylamino}pyrid- azin-3-yl)benzamide

466.1 D (tert-butoxy)-N-[2-(3-fluoro(2-pyridyl))-2-methylpropyl]-N-[6-(2- hydroxybenzimidazol-5-yl)pyridazin-3-yl]carboxamide

479.1 D 5-(6-{[2-(3-fluoro(2-pyridyl))-2-methylpropyl]amino}pyridazin-3- yl)benzimidazol-2-ol

379.1 A (6-(1H-indazol-5-yl)pyridazin-3- yl)[2-(3-fluoro(2-pyridyl))-2-methylpropyl]amine

363.1 B N-[6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)benzimidazol-2-yl]acetamide

419.1 A 6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1,3-dihydroquinazoline-2,4- dione

406.1 B 4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]benzamide

378.0 B 4-fluoro-3-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

396.2 A (6-(1H-indazol-5-yl)pyridazin-3- yl){[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

375.0 A 2-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)pyridine-4-carboxamide

366.0 A 6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)pyridine-2-carboxamide

366.1 B 3-(6-{(tert-butoxy)-N-[2-(4- fluorophenyl)-2-methylpropyl]carbonylamino}py- ridazin-3-yl)benzamide

465.3 D 3-(6-{(tert-butoxy)-N-[2-(4- fluorophenyl)-2-methylpropyl]carbonylamino}py- ridazin-3-yl)-4-fluorobenzamide

483.3 D (6-(1H-indazol-6-yl)pyridazin-3- yl){[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

375.0 A (6-(1H-indazol-6-yl)pyridazin-3- yl){[(6-methoxy(2-pyridyl))cyclobutyl]methyl}amine

387.1 A (6-(1H-indazol-5-yl)pyridazin-3- yl){[(6-methoxy(2-pyridyl))cyclobutyl]methyl}amine

387.1 A 4-fluoro-3-[6-({[(6-methoxy(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

408.1 A 4-fluoro-3-(6-{[(2- pyridylcyclobutyl)methyl]amino}py-ridazin-3-yl)benzamide

378.1 A (6-(1H-indazol-5-yl)pyridazin-3- yl)[(2-pyridylcyclobutyl)methyl]amine

357.2 A (6-(1H-indazol-6-yl)pyridazin-3- yl)[(2-pyridylcyclobutyl)methyl]amine

357.2 A 2-fluoro-3-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

396.0 B 3-fluoro-4-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

396.0 B 2-fluoro-4-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)benzoic acid

384.1 D methyl 3-amino-5-(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)-1H-indazolecarboxylate

435.1 B methyl 5-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)-3-(methoxycarbonylamino)-1H-indazolecarboxylate

493.1 C N-[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)(1H-indazol-3- yl)]methoxycarboxamide

435.1 A [3-amino-5-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)(1H-indazolyl)]-N,N-dimethylcarboxamide

448.1 B 6-({[(6-(1H-indazol-5-yl)pyridazin-3-yl)amino]methyl}cyclobutyl) pyridin-2-ol

373.1 D 6-({[(6-(1H-indazol-6-yl)pyridazin-3-yl)amino]methyl}cyclobutyl) pyridin-2-ol

373.1 D 4-fluoro-3-[6-({[(6-hydroxy(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

394.1 D 2-({[(6-(1H-indazol-5-yl)pyridazin-3-yl)amino]methyl}cyclobutyl) pyridin-4-ol

373.1 D 4-fluoro-3-[6-({[(4-methoxy(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

408.2 B (6-(1H-indazol-5-yl)pyridazin-3- yl){[(4-methoxy(2-pyridyl))cyclobutyl]methyl}amine

387.2 A (6-(1H-indazol-6-yl)pyridazin-3- yl){[(4-methoxy(2-pyridyl))cyclobutyl]methyl}amine

387.2 A 2-({[(6-(1H-indazol-6-yl)pyridazin-3-yl)amino]methyl}cyclobutyl) pyridin-4-ol

373.2 D 4-fluoro-3-[6-({[(4-hydroxy(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

394.2 D 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-3-hydrobenzimidazol- 2-one

391.0 B {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-pyrazol-4-ylpyridazin-3-yl)amine

325.0 C {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(1-methylpyrazol-4-yl)pyridazin-3- yl]amine

339.0 D 6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-3,3-dimethylindolin-2-one

405.0 D 2-amino-7-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)-3-hydroquinazolin-4-one

405.1 C 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]benzenesulfonamide

414.4 A {4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3- yl]phenyl}(methylsulfonyl)amine

428.3 B {3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3- yl]phenyl}(methylsulfonyl)amine

428.3 B 3-{6-[(2-methyl-2-pyrimidin-2- ylpropyl)amino]pyridazin-3-yl}benzamide

349.0 D 4-fluoro-3-[6-({[(3-methoxy(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

408.2 B (6-(1H-indazol-5-yl)pyridazin-3- yl){[(3-methoxy(2-pyridyl))cyclobutyl]methyl}amine

387.2 B (6-(1H-indazol-6-yl)pyridazin-3- yl){[(3-methoxy(2-pyridyl))cyclobutyl]methyl}amine

387.1 B 4-fluoro-3-[6-({[(5-methoxy(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

408.1 D (6-(1H-indazol-5-yl)pyridazin-3- yl){[(5-methoxy(2-pyridyl))cyclobutyl]methyl}amine

387.2 B (6-(1H-indazol-6-yl)pyridazin-3- yl){[(5-methoxy(2-pyridyl))cyclobutyl]methyl}amine

387.2 B 3-{[(6-(1H-indazol-6-yl)pyridazin- 3-yl)amino]methyl}-3-(2-pyridyl)cyclobutan-1-ol

373.1 D 3-{[(6-(1H-indazol-6-yl)pyridazin- 3-yl)amino]methyl}-3-(2-pyridyl)cyclobutan-1-ol

373.2 D 3-[6-({[(4- fluorophenyl)cyclobutyl]meth-yl}amino)pyridazin-3-yl]benzamide

377.3 A 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-4-methylbenzamide

392.3 B 6-({[(6-(1H-indazol-5-yl)pyridazin-3-yl)amino]methyl}cyclobutyl) pyridine-3-carbonitrile

382.2 B 6-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-3,3-dimethylindolin- 2-one

418.0 D 3-[6-({[(4-cyano-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]benzamide

385.1 B 2-[({[6-(3- carbamoylphenyl)pyridazin-3-yl]amino}methyl)cyclobutyl]py- ridine-4-carboxamide

403.2 D 3-[6-({[(4-cyano(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-y]-4-fluorobenzamide

403.1 B 2-[({[6-(3-carbamoyl-6- fluorophenyl)pyridazin-3-yl]amino}methyl)cyclobutyl]py- ridine-4-carboxamide

421.2 D 2-({[(6-(1H-indazol-5-yl)pyridazin-3-yl)amino]methyl}cyclobutyl) pyridine-4-carbonitrile

382.1 A 2-({[(6-(1H-indazol-5-yl)pyridazin-3-yl)amino]methyl}cyclobutyl) pyridine-4-carboxamide

400.2 C 3-[6-({[(6-cyano-2- pyridyl)cycIobutyl]methyl}amino)py-ridazin-3-yl]benzamide

385.1 B 6-[({[6-(3- carbamoylphenyl)pyridazin-3-yl]amino}methyl)cyclobutyl]py- ridine-2-carboxamide

403.2 D 6-({[(6-(1H-indazol-5-yl)pyridazin-3-yl)amino]methyl}cyclobutyl) pyridine-2-carbonitrile

382.1 B 6-({[(6-(1H-indazol-5-yl)pyridazin-3-yl)amino]methyl}cyclobutyl) pyridine-2-carboxamide

400.1 B (6-(1H-indazol-6-yl)pyridazin-3- yl){[(4-fluorophenyl)cyclobutyl]meth- yl}amine

374.1 A (6-(1H-indazol-5-yl)pyridazin-3- yl){[(4-fluorophenyl)cyclobutyl]meth- yl}amine

374.1 A 4-fluoro-3-[6-({[(1-methyl-6-oxo(2-hydropyridyl))cyclobutyl]meth- yl}amino)pyridazin-3-yl]benzamide

408.1 D 3-(6-{[(2- pyridylcyclobutyl)methyl]amino}py-ridazin-3-yl)benzamide

360.2 A ({[(6-(1H-indazol-5-yl)pyridazin-3-yl)amino]methyl}cyclobutyl)methan- 1-ol

310.2 D 1-({[6-(3-cyanophenyl)pyridazin-3-yl]amino}methyl)cyclobutanecar- boxylic acid

309.2 D 1-({[6-(3- carbarnoylphenyl)pyridazin-3-yl]amino}methyl)cyclobutanecar- boxylic acid

327.2 D 1-({[6-(3-cyanophenyl)pyridazin-3-yl]amino}methyl)cyclobutanecar- boxamide

308.2 D 3-(6- {[(carbamoylcyclobutyl)meth-yl]amino}pyridazin-3-yl)benzamide

326.2 D methyl 3-(3-fluoro(2-pyridyl))-3-{[(6-(1H-indazol-5-yl)pyridazin-3- yl)amino]methyl}azetidinecar-boxylate

434.2 D methyl 3-({[6-(3- carbamoylphenyl)pyridazin-3-yl]amino}methyl)-3-(3-fluoro(2- pyridyl))azetidinecarboxylate

437.2 D {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[3-(methylamino)(1H-indazol-5- yl)]pyridazin-3-yl}amine

404.1 A 2-fluoro-5-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzoic acid

397.0 B {2-fluoro-5-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-methylcarboxamide

410.0 B N-{5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1H-indazol-3- yl}acetamide

432.2 B 2-amino-N-{5-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1H-indazol-3-yl)}acetamide

447.2 B {5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1H-indazol-3- yl)}(methylsulfonyl)amine

468.2 A 3-amino-5-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-1H-indazolecarboxamide

433.3 B [6-(3-aminophenyl)pyridazin-3- yl]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

350.2 A [6-(4-aminophenyl)pyridazin-3- yl]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

350.2 A (6-{3-[(2-aminoethyl)aminol](1H-indazol-5-yl)}pyridazin-3-yl){[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine

433.0 A amino{3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3- yi]phenyl}carboxamidine

392.2 B amino{4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3- yl]phenyl}carboxamidine

392.2 B 3-(6-{[(pyrazin-2- ylcyclobutyl)methyl]amino}py-ridazin-3-yl)benzamide

361.3 D (6-(1H-indazol-6-yl)pyridazin-3- yl)[(pyrazin-2-ylcyctobutyl)methyl]amine

358.3 C (6-(1H-indazol-5-yl)pyridazin-3- yl)[(pyrazin-2-ylcyclobutyl)methyl]amine

358.3 C amino-N-{3-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}amide

393.2 A 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]benzene-1,3- dicarboxylic acid

423.2 D 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]benzene-1,3- dicarboxamide

421.2 B 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3- yl]benzenecarboxamidine

377.2 D 3-[6-({[1-acetyl-3-(3-fluoro(2- pyridyl))azetidin-3-yl]methyl}amino)pyridazin-3- yl]benzamide

421.2 D 1-acetyl-3-(3-fluoro(2-pyridyl))-3-{[(6-(1H-indazol-5-yl)pyridazin-3- yl)amino]methyl}azetidine

418.2 D (6-(1H-indazol-5-yl)pyridazin-3-yl){[3-(3-fluoro(2-pyridyl))azetidin- 3-yl]methyl}amine

376.2 D 3-[6-({[3-(3-fluoro-2- pyridyl)azetidin-3-yl]methyl}amino)pyridazin-3- yl]benzamide

379.2 D 3-(3-fluoro(2-pyridyl))-3-{[(6-(1H- indazol-5-yl)pyridazin-3-yl)amino]methyl}-1- (methylsulfonyl)azetidine

454.2 D 3-[6-({[3-(3-fluoro(2-pyridyl))-1- (methylsulfonyl)azetidin-3-yl]methyl}amino)pyridazin-3- yl]benzamide

457.2 D (6-(1H-indazol-5-yl)pyridazin-3-yl){[3-(3-fluoro(2-pyridyl))azetidin- 3-yl]methyl}(methylsulfonyl)amine

454.2 D amino{5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1H-indazol-3- yl)}carboxamidine

432.2 B 3-[6-({[3-(4-fluorophenyl)oxetan-3- yl]methyl}amino)pyridazin-3-yl]benzamide

379.0 D [2-(4-fluorophenyl)-2- methylpropyl](6-{3-[(methylethyl)amino](1H-indazol- 5-yl)}pyridazin-3-yl)amine

419.3 A [6-(2-aminopyrimidin-5- yl)pyridazin-3-yl][2-(4-fluorophenyl)-2- methylpropyl]amine

339.2 B [2-(4-fluorophenyl)-2- methylpropyl]{6-[3-(methylamino)(1H-indazol-5- yl)]pyridazin-3-yl}amine

391.3 B [2-(4-fluorophenyl)-2- methylpropyl][6-(2-methoxypyrimidin-5-yl)pyridazin-3- yl]amine

354.2 C [2-(4-fluorophenyl)-2- methylpropyl][6-(2-methoxy(3-pyridyl))pyridazin-3-yl]amine

353.1 A {6-[3-(ethylamino)(1H-indazol-5- yl)]pyridazin-3-yl}[2-(4-fluorophenyl)-2- methylpropyl]amine

405.2 A [2-(4-fluorophenyl)-2- methylpropyl](6-phenylpyridazin-3-yl)amine

322.2 A 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)hydropyridin-2-one

339.2 B [6-(2-amino(4-pyridyl))pyridazin-3- yl][2-(4-fluorophenyl)-2-methylpropyl]amine

338.2 B [6-(4-aminophenyl)pyridazin-3- yl][2-(4-fluorophenyl)-2-methylpropyl]amine

337.1 A [6-(3-aminophenyl)pyridazin-3- yl][2-(4-fluorophenyl)-2-methylpropyl]amine

337.1 A 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)pyridin-2-ol

339.1 B 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-3-hydropyrimidin-2-one

340.1 D 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1,3,4-oxadiazolin-2-one

330.0 C [6-(6-amino(3-pyridyl))pyridazin-3- yl][2-(4-fluorophenyl)-2-methylpropyl]amine

338.2 A [2-(4-fluorophenyl)-2- methylpropyl](6-vinylpyridazin-3-yl)amine

272.0 B [6-(5-aminopyrazol-3-yl)pyridazin- 3-yl][2-(4-fluorophenyl)-2-methylpropyl]amine

327.2 B [2-(4-fluorophenyl)-2- methylpropyl][6-(6-methoxy(2-pyridyl))pyridazin-3-yl]amine

353.1 A N-[4-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)imidazol-2-yl]acetamide

369.2 C 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)pyridine-2-carbonitrile

348.0 C [6-(2-aminoimidazol-4- yl)pyridazin-3-yl][2-(4- fluorophenyl)-2-methylpropyl]amine

327.2 B 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)pyridine-2-carboxamide

366.1 B 6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)pyridin-2-ol

339.1 B {6-[6-(aminomethyl)(3- pyridyl)]pyridazin-3-yl}[2-(4-fluorophenyl)-2- methylpropyl]amine

352.2 B [2-(4-fluorophenyl)-2- methylpropyl][6-(2-fluorophenyl)pyridazin-3-yl]amine

340.1 A [2-(4-fluorophenyl)-2- methylpropyl][6-(3-fluorophenyl)pyridazin-3-yl]amine

340.1 A [2-(4-fluorophenyl)-2- methylpropyl][6-(4-fluorophenyl)pyridazin-3-yl]amine

340.1 B [6-(2-chlorophenyl)pyridazin-3- yl][2-(4-fluorophenyl)-2-methylpropyl]amine

356.1 A [6-(3-chlorophenyl)pyridazin-3- yl][2-(4-fluorophenyl)-2-methylpropyl]amine

356.1 A [6-(4-chlorophenyl)pyridazin-3- yl][2-(4-fluorophenyl)-2-methylpropyl]amine

356.1 B 4-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)benzenecarbonitrile

347.1 B [2-(4-fluorophenyl)-2- methylpropyl](6-(3-pyridyl)pyridazin-3-yl)amine

323.1 B [6-(6-amino(2-pyridyl))pyridazin-3- yl][2-(4-fluorophenyl)-2-methylpropyl]amine

338.2 B N-{[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-2-pyridyl]methyl}acetamide

394.2 C N-{[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)(2- pyridyl)]methyl}methoxycar- boxamide

410.2 C {6-[3-(ethylamino)(1H-indazol-5-yl)]pyridazin-3-yl}{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine

418.2 A 3-(6-{[2-methyl-2- (phenylmethoxy)propyl]amino}py-ridazin-3-yl)benzamide

377.0 D 3-(6-{[2-methyl-2- (phenylmethoxy)propyl]amino}py-ridazin-3-yl)benzenecarbonitrile

359.0 D [2-(4-fluorophenyl)-2- methylpropyl](6-(2-pyridyl)pyridazin-3-yl)amine

323.1 B N-{4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]imidazol-2- yl]acetamide

382.1 D [6-(2-aminoimidazol-4- yl)pyridazin-3-yl]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

340.1 D {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-{3-[(methylethyl)amino](1H-indazol- 5-yl)}pyridazin-3-yl)amine

432.2 A {6-[3-(ethylamino)(1H-indazol-5- yl)]pyridazin-3-yl}[(2-pyridylcyclobutyl)methyl]amine

400.2 A [6-((1E)prop-1-enyl)pyridazin-3- yl][2-(4-ftuorophenyl)-2-methylpropyl]amine

286.0 B [2-(4-fluorophenyl)-2- methylpropyl][6-(2-methylprop-1-enyl)pyridazin-3-yl]amine

300.0 B [2-(4-fluorophenyl)-2- methylpropyl][6-(2-methylpropyl)pyridazin-3-yl]amine

302.0 B ethyl 3-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)propanoate

346.0 D 6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)pyridine-3-carboxamide

366.1 B (6-ethylpyridazin-3-yl)[2-(4- fluorophenyl)-2-methylpropyl]amine

274.0 C [3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)phenyl]methan-1-ol

352.2 B (tert-butoxy)-N-{[3-(6-{[2-(4- fluorophenyl)-2-methylpropyl]amino}pyridazin-3- yl)phenyl]methyl}carboxamide

451.1 B {6-[3- (aminomethyl)phenyl]pyridazin-3-yl}[2-(4-fluorophenyl)-2- methylpropyl]amine

351.2 B {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[2-(trifluoromethoxy)phenyl]pyridazin-3- yl}amine

419.1 A {2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]phenyl}methan-1-ol

365.2 B [2-(4-fluorophenyl)-2- methylpropyl][6-(5-methoxy(2-pyridyl))pyridazin-3-yl]amine

353.2 B 6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)pyridin-3-ol

339.1 A [6-(5-amino(2-pyridyl))pyridazin-3- yl]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

351.2 A [2-(4-fluorophenyl)-2- methylpropyl](6-{3-[(2,2,2-trifluoroethyl)amino](1H-indazol-5- yl)}pyridazin-3-yl)amine

459.2 A [6-(6-amino(3-pyridyl))pyridazin-3- yl]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

351.2 A [6-(4-amino-3- fluorophenyl)pyridazin-3-yl]{[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine

368.1 A (6-benzotriazol-6-ylpyridazin-3- yl){[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

376.1 A 4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]indolin-2-one

390.1 B (6-benzimidazol-5-ylpyridazin-3- yl){[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

375.1 A N-{3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl)methyl}amino)py-ridazin-3-yl]phenyl}acetamide

392.2 B {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(4-morpholin-4-ylphenyl)pyridazin-3- yl]amine

420.2 D {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(2-methylpyrimidin-5-yl)pyridazin-3- yl]amine

351.2 D [5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)(1H-indazol-3-yl)]dimethylamine

405.2 B [2-(4-fluorophenyl)-2- methylpropyl][6-(3-{[2-(phenylmethoxy)ethyl]amino}(1H- indazol-5-yl))pyridazin-3-yl]amine

511.2 A 2-{[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl)-1H-indazol-3-yl]amino}ethan-1- ol

421.2 A {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-pyrimidin-2-ylpyridazin-3-yl)amine

337.0 B {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-pyrazin-2-ylpyridazin-3-yl)amine

337.0 B ethyl 6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazine-3-carboxylate

331.0 D 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]propan-2-ol

317.0 D {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-phenylpyridazin-3-yl)amine

335.1 A {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-vinylpyridazin-3-yl)amine

285.1 D (6-ethylpyridazin-3-yl){[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

287.1 D N-{4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]phenyl}acetamide

392.2 A [6-(2-aminopyrimidin-5- yl)pyridazin-3-yl]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

352.1 B N-{5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]pyrimidin-2- yl}acetamide

394.2 C N-{5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]pyrimidin-2- yl}methoxycarboxamide

410.1 D {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(5-methoxy(2-pyridyl))pyridazin-3- yl]amine

366.2 B 6-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]pyridin-3-ol

352.1 A {5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]pyrimidin-2- yl}(methylsulfonyl)amine

430.0 D [6-(2,3-difluorophenyl)pyridazin-3- yl]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

371.0 A {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(3-fluoro(2-pyridyl))pyridazin-3- yl]amine

354.0 B 3-{6-[(1-methyl-1- phenylethyl)amino]pyridazin-3- yl}benzamide

333.2 B 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]indolin-2-one

390.1 B 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1H-2-hydroindazol-3- one

391.1 A N-{3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3- yl]phenyl}(methylamino)car- boxamide

407.2 A N-{4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3- yl]phenyl}(methylamino)car- boxamide

407.2 A tert-butyl 4-{5-[6-({[(3-fluoro-2-pyridyl)cyclobutyl]methyl}amino)py- ridazin-3-yl]pyrimidin-2-yl}piperazinecarboxylate

521.3 D 2-({5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]pyrimidin-2- yl}amino)acetamide

409.1 C {6-[2-(aminomethyl)-5- fluorophenyl]pyridazin-3-yl}{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine

382.2 C {6-[2- (aminomethyl)phenyl]pyridazin-3- yl}{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

364.2 D {6-[4- (aminomethyl)phenyl]pyridazin-3- yl}{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

364.2 B {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(2-piperazinylpyrimidin-5- yl)pyridazin-3-yl]amine

421.2 D (6-(1H-indazol-6-yl)pyridazin-3- yl)(2,2-difluoro-2-(2-pyridyl)ethyl)amine

353.1 D 3-{6-[(2,2-difluoro-2-(2- pyridyl)ethyl)amino]pyridazin-3-yl}benzamide

356.1 D [6-(3-chloro(2-pyridyl))pyridazin-3- yl]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

370.1 C 6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazine-3-carbonitrile

284.0 D 1-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]ethan-1-one

301.1 D {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(2-methyl(3-pyridyl))pyridazin-3- yl]amine

350.2 C 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]pyridine-2-carbonitrile

361.1 C 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]pyridine-2- carboxamide

379.2 C methyl 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]pyridine-2-carboxylate

394.2 C 2-{3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-pyridyl}propan-2-ol

394.2 D amino-N-{4-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}amide

393.0 A 2-amino-2-{3-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}acetamide

407.0 C {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-pyridazin-4-ylpyridazin-3-yl)annine

337.2 D 3-[6-({[3,3-difluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

414.0 B (6-(1H-indazol-5-yl)pyridazin-3-yl){[3,3-difluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine

411.0 B 5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-(methylethyl)-1H- 2-hydroindazol-3-one

433.1 B 5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-1-(methylethyl)-1H- 2-hydroindazol-3-one

433.1 C 3-{6-[(1-methyl-1- phenylethyl)amino]pyridazin-3-yl}benzenecarbonitrile

315.0 B 3-{6-[(tert-butyl)amino]pyridazin-3- yl}benzamide

271.1 C 3-[6- (phenylcarbonylamino)pyridazin- 3-yl]benzamide

319.1 D {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-(2-pyridyl)pyridazin-3-yl)amine

336.1 B 3-{6-[(1-methyl-1-(2- pyridyl)ethyl)amino]pyridazin-3-yl}benzamide

334.1 D {3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-pyridyl}methan-1-ol

366.2 C 3-(6-{[(4- fluorophenyl)cyclobutyl]amino}py-ridazin-3-yl)benzamide

363.1 A (6-(1H-indazol-5-yl)pyridazin-3- yl)[(4-fluorophenyl)cyclobutyl]amine

360.1 A 4-{6-[(1-methyl-1- phenylethyl)amino]pyridazin-3- yl}benzamide

333.1 C (6-(1H-indazol-5-yl)pyridazin-3-yl)(1-methyl-1-phenylethyl)amine

330.2 B [6-(6-amino(3-pyridyl))pyridazin-3-yl](1-methyl-1-phenylethyl)amine

306.2 B amino-N-{5-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](2-pyridyl)}amide

394.2 B (1-methyl-1-phenylethyl)(6- phenylpyridazin-3-yl)amine

290.1 B 1-amino-1-{4-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-2-methylpropan-2-ol

422.2 D amino-N-{5-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]pyrimidin-2-yl}amide

395.2 D (6-(1H-indazol-6-yl)pyridazin-3-yl){[3,3-difluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine

411.1 B [6-(2-amino(3-pyridyl))pyridazin-3- yl]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

351.1 B [6-(6-amino-5-fluoro(3- pyridyl))pyridazin-3-yl]{[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine

369.1 A 6-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]indolin-2-one

390.1 B [6-(2-aminopyrimidin-5- yl)pyridazin-3-yl][(4-fluorophenyl)cyclobutyl]amine

337.0 B amino-N-[4-(6-{[(4- fluorophenyl)cyclobutyl]amino}py-ridazin-3-yl)phenyl]amide

378.2 A amino-N-{4-[6-({[3,3-difluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}amide

429.0 A 3-(6-{[1-(4-fluorophenyl)- isopropyl]amino}pyridazin-3-yl)benzamide

351.1 B 3-(6-{[(2- fluorophenyl)cyclobutyl]amino}py-ridazin-3-yl)benzamide

363.2 A 3-(6-{[1-(3-fluorophenyl)- isopropyl]amino}pyridazin-3-yl)benzamide

351.1 B 3-(6-{[(3- fluorophenyl)cyclobutyl]amino}py-ridazin-3-yl)benzamide

363.2 B 3-{6-[(2-hydroxy-tert- butyl)amino]pyridazin-3- yl}benzamide

287.1 D 3-{6-[(2- pyridylcyclobutyl)amino]pyridazin- 3-yl}benzamide

346.1 D (phenylcyclobutyl)(6- phenylpyridazin-3-yl)amine

302.2 B 3-{6- [(phenylcyclobutyl)amino]pyridazin-3- yl}benzamide

345.1 B 3-(6-{[(3-fluoro-2- pyridyl)cyclobutyllamino}pyridazin-3-yl)benzamide

364.1 B 3-(6-{[(5-fluoro-2- pyridyl)cyclobutyl]amino}pyridazin-3-yl)benzamide

364.1 B 4-fluoro-3-(6-{[(4- fluorophenyl)cyclobutyl]amino}py-ridazin-3-yl)benzamide

381.1 A [(4-fluorophenyl)cyclobutyl][6-(6-methoxy(2-pyridyl))pyridazin-3- yl]amine

351.1 B (6-benzimidazol-5-ylpyridazin-3- yl)[(4-fluorophenyl)cyclobutyl]amine

360.1 A [(4-fluorophenyl)cyclobutyl](6- pyrazol-4-ylpyridazin-3-yl)amine

310.1 B 3-{6-[(1,3-thiazol-2- ylcyclobutyl)amino]pyridazin-3-yl}benzamide

352.2 D 4-fluoro-3-(6-{[(3-fluoro(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)benzamide

382.1 B 4-fluoro-3-(6-{[1-(4-fluorophenyl)- isopropyl]amino}pyridazin-3-yl)benzamide

369.1 A 3-(6-{[(4-methoxy-2- pyridyl)cyclobutyl]amino}pyridazin-3-yl)benzamide

376.0 D [6-(3-fluoro(4-pyridyl))pyridazin-3- yl][(4-fluorophenyl)cyclobutyl]amine

339.2 B [(4-fluorophenyl)cyclobutyl](6-(4- pyridyl)pyridazin-3-yl)amine

321.2 B 4-(6-{[(4- fluorophenyl)cyclobutyl]amino}py-ridazin-3-yl)pyridine-2-carbonitrile

346.2 B 4-(6-{[(4- fluorophenyl)cyclobutyl]amino}py-ridazin-3-yl)pyridine-2-carboxamide

364.2 B [4-(6-{[(4- fluorophenyl)cyclobutyl]amino}py- ridazin-3-yl)phenyl](methylsulfonyl)amine

413.1 B [(4-fluorophenyl)cyclobutyl][6-(2-methoxy(3-pyridyl))pyridazin-3- yl]amine

351.2 A [(4-fluorophenyl)cyclobutyl]{6-[2- (2,2,2-trifluoroethoxy)(3-pyridyl)]pyridazin-3-yl}amine

419.2 B 3-(6-{[(4- chlorophenyl)cyclobutyl]amino}py-ridazin-3-yl)benzamide

379.1 B 3-(6-{[(4- cyanophenyl)cyclobutyl]amino}py-ridazin-3-yl)benzamide

370.1 D 3-(6-{[(3-chloro(2- pyridyl))cyclobutyl]amino}pyridazin-3-yl)-4-fluorobenzamide

398.1 A [3-(6-{[(4- fluorophenyl)cyclobutyl]amino}py- ridazin-3-yl)phenyl](methylsulfonyl)amine

413.0 A 3-(6-{[(4- carbamoylphenyl)cyclobutyl]ami-no}pyridazin-3-yl)benzamide

388.2 D [(4-fluorophenyl)cyclobutyl][6-(2-methyl(4-pyridyl))pyridazin-3- yl]amine

335.2 B [(4-fluorophenyl)cyclobutyl][6-(2-methoxy(4-pyridyl))pyridazin-3- yl]amine

351.2 B 3-(6-{[(6-methoxy-2- pyridyl)cyclobulyl]amino}pyridazin-3-yl)benzamide

376.1 B 4-fluoro-3-(6-{[(6-methoxy(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)benzamide

394.1 A [3-(6-{[(6-methoxy(2- pyridyl))cyclobutyl]amino}pyridazin-3-yl)phenyl](methylsulfonyl)amine

426.1 B [3-(6-{[(3-fluoro(2- pyridyl))cyclobutyl]amino}pyridazin-3-yl)phenyl](methylsulfonyl)amine

414.1 B amino-N-[4-(6-{[(3-fluoro(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)phenyl]amide

379.2 B (6-(1H-indazol-6-yl)pyridazin-3- yl)[(3-fluoro(2-pyridyl))cyclobutyl]amine

361.1 B (6-benzimidazol-6-ylpyridazin-3- yl)[(3-fluoro(2-pyridyl))cyclobutyl]amine

361.2 B 3-[6-({[6-(difluoromethoxy)-2-pyridyl]cyclobutyl}amino)pyridazin- 3-yl]benzamide

412.0 A 3-[6-({[6-(difluoromethoxy)(2-pyridyl)]cyclobutyl}amino)pyridazin- 3-yl]-4-fluorobenzamide

430.1 A {3-[6-({[6-(difluoromethoxy)(2-pyridyl)]cyclobutyl}amino)pyridazin- 3-yl]phenyl}(methylsulfonyl)amine

462.1 A 4-fluoro-3-(6-{[(4- fluorophenyl)cyclobutyl]amino}py-ridazin-3-yl)benzoic acid

382.2 B [4-fluoro-3-(6-{[(4- fluorophenyl)cyclobutyl]amino}py-ridazin-3-yl)phenyl]-N-(2-hydroxy-2- methylpropyl)carboxamide

453.2 B 3-(6-{[(3-bromo(2- pyridyl))cyclobutyl]amino}pyridazin-3-yl)-4-fluorobenzamide

442.1 A 3-(6-{[1-(3-chloro(2-pyridyl))-isopropyl]amino}pyridazin-3-yl)-4- fluorobenzamide

386.1 B 4-chloro-3-(6-{[(3-fluoro(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)benzamide

398.1 B [4-(6-{[(4- fluorophenyl)cyclobutyl]amino}py-ridazin-3-yl)(2-pyridyl)]-N- methylcarboxamide

378.2 B (6-(1H-indazol-5-yl)pyridazin-3- yl)[(3-fluoro(2-pyridyl))cyclobutyl]amine

361.1 B [6-(6-fluoro(1H-indazol-5- yl))pyndazin-3-yl][(3-fluoro(2-pyridyl))cyclobutyl]amine

379.1 B amino-N-[4-fluoro-3-(6-{[(3- fluoro(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)phenyl]amide

398.1 B amino[4-fluoro-3-(6-{[(3-fluoro(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)phenyl]sulfonamide

433.1 B amino[3-fluoro-4-(6-{[(3-fluoro(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)phenyl]sulfonamide

433.1 B amino-N-[3-fluoro-4-(6-{[(3- fluoro(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)phenyl]amide

397.1 B 4-fluoro-3-(6-{[1-methyl-1-(6- oxo(2-hydropyridyl))ethyl]amino}py- ridazin-3-yl)benzamide

368.2 D 3-[6-({1-[6-(difluoromethoxy)(2- pyridyl)]-isopropyl}amino)pyridazin-3-yl]-4- fluorobenzamide

418.1 A 3-[6-({1-[6-(difluoromethoxy)(2- pyridyl)]-isopropyl}amino)pyridazin-3- yl]benzamide

400.2 B {3-[6-({1-[6-(difluoromethoxy)(2- pyridyl)]-isopropyl}amino)pyridazin-3- yl]phenyl}(methylsulfonyl)amine

450.1 A 3-(6-{[(4-cyano(2- pyridyl))cyclobutyl]amino}pyridazin-3-yl)-4-fluorobenzamide

389.1 D 2-({[6-(3-carbamoyl-6- fluorophenyl)pyridazin-3-yl]amino}cyclobutyl)pyridine-4- carboxamide

407.1 D 3-(6-{[(5-cyano(2- pyridyl))cyclobutyl]amino}pyridazin-3-yl)-4-fluorobenzamide

389.2 D 3-(6-{[(6-cyano(2- pyridyl))cyclobutyl]amino}pyridazin-3-yl)-4-fluorobenzamide

389.2 B 6-({[6-(3-carbamoyl-6- fluorophenyl)pyridazin-3-yl]amino}cyclobutyl)pyridine-2- carboxamide

407.2 D 4-fluoro-3-(6-{[(3-hydroxy(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)benzamide

380.2 D 4-fluoro-3-(6-{[(3-methoxy(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)benzamide

394.2 C 3-[6-({[3-(difluoromethoxy)(2-pyridyl)]cyclobutyl}amino)pyridazin- 3-yl]-4-fluorobenzamide

430.2 C 3-[6-({[3-(difluoromethoxy)-2-pyridyl]cyclobutyl}amino)pyridazin- 3-yl]benzamide

412.2 D {3-[6-({[3-(difluoromethoxy)(2-pyridyl)]cyclobutyl}amino)pyridazin- 3-yl]phenyl}(methylsulfonyl)amine

462.2 C 4-fluoro-3-(6-{[(5-methoxy(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)benzamide

394.2 D 3-[6-({[5-(difluoromethoxy)(2-pyridyl)]cyclobutyl}amino)pyridazin- 3-yl]-4-fluorobenzamide

430.1 D 4-fluoro-3-(6-{[(5-hydroxy(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)benzamide

380.1 D [(3-fluoro(2-pyridyl))cyclobutyl](6- vinylpyridazin-3-yl)amine

271.1 D 4-fluoro-3-(6-{[(3-fluoro(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)benzenecarbonitrile

364.1 B [(3-fluoro(2-pyridyl))cyclobutyl](6- phenylpyridazin-3-yl)amine

321.1 B (6-cyclohexylpyridazin-3-yl)[(3-fluoro(2-pyridyl))cyclobutyl]amine

327.2 C (6-cyclohex-1-enylpyridazin-3- yl)[(3-fluoro(2-pyridyl))cyclobutyl]amine

325.2 C (6-cyclohex-1-enylpyridazin-3- yl){[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

339.2 A 4-fluoro-3-{6- [(methylcyclobutyl)amino]pyridazin-3-yl}benzamide

301.1 D (6-cyclohexylpyridazin-3-yl){[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine

341.2 B ethyl (2E)-3-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]prop-2-enoate

357.2 D ethyl (2E)-3-(6-{[(3-fluoro(2-pyridyl))cyclobutyl]amino}pyridazin- 3-yl)prop-2-enoate

343.1 D diethyl 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]propane-1,3-dioate

417.2 D (1S,2S)-2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]cyclopropanecarboxamide

342.2 D (2S,1R)-2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]cyclopropanecarboxamide

342.2 D amino-N-{4-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]cyclohexyl}amide

399.3 B amino-N-{4-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]cyclohexyl}amide

399.2 C 4-fluoro-3-(6-{[(3-fluoro(2-pyridyl))cyclopentyl]amino}pyridazin- 3-yl)benzamide

396.2 A amino-N-{3-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]cyclobutyl}amide

371.2 C amino-N-{3-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]cyclobutyl}amide

371.2 B amino-N-{4-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]cyclohex-3- enyl}amide

397.2 B phenylmethyl 3-[6-({[(3-fluoro-2-pyridyl)cyclobutyl]methyl}amino)py- ridazin-3-yl]azetidinecarboxylate

448.2 D (6-azetidin-3-ylpyridazin-3-yl){[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine

314.2 D methyl 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]azetidinecarboxylate

372.2 D 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]azetidinecarboxamide

357.2 D 1-acetyl-3-[6-({((3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]azetidine

356.2 D ethyl 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]isoxazole-3- carboxylate

398.2 D 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]isoxazole-3-carboxylic acid

370.2 D 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]isoxazole-3- carboxamide

369.2 B amino-N-{5-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1H-indazol-3-yl)}amide

433.3 A 4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-1-methylimidazoJe-2- carboxamide

382.3 D 4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2- methoxybenzamide

408.2 B 4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-hydroxybenzamide

394.1 B 5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2- methoxybenzamide

408.2 B 5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-hydroxybenzamide

394.1 A 4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-methoxybenzoic acid

409.2 D 5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-methoxybenzoic acid

409.2 D 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-oxazole-2- carboxamide

369.2 B 4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]imidazole-2- carboxamide

368.2 C 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]isoxazole-5- carboxamide

369.2 A 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]pyrazole-5- carboxamide

368.3 B 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-1-methylpyrazole-5- carboxamide

382.3 B 5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-1-methylpyrazole-3- carboxamide

382.3 B 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-oxazole-5- carboxamide

369.1 B 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazole-4- carboxamide

385.1 D 1-[(6-{[(3-fluoro-2- pyridyl)cyclobutyl]amino}pyridazin-3-yl)methyl]pyrazole-4- carboxamide

368.1 D 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,2,4-oxadiazole-3- carboxamide

370.2 B 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-imidazoline-5- carboxamide

370.3 D methyl 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-imidazoline-5- carboxylate

385.3 D 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-imidazoline-5- carboxylic acid

371.3 D 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-oxazole-4- carboxamide

369.2 D 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazole-5- carboxamide

385.2 A methyl 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-oxazole-4- carboxylate

384.2 D {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[6- ({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]pyridazin-3-yl}amine

515.4 D methyl 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazole-4- carboxylate

400.2 D methyl 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-oxazole-5- carboxylate

384.2 D 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]imidazole-4- carboxamide

368.2 B methyl 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]imidazole-4- carboxylate

383.3 D 4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazole-2- carboxamide

385.2 B 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazole-2- carboxamide

385.2 B 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,2,4-oxadiazole-5- carboxamide

370.1 B 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-4H-1,2,4-triazole-3- carboxamide

369.2 C methyl 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-1-methylimidazole-4- carboxylate

397.3 D 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-1-methylimidazole-4- carboxamide

382.3 D 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-1-methylimidazole-5- carboxamide

382.3 B 2-(6-{[(3-fluoro-2- pyridyl)cyclobutyl]amino}pyridazin-3-yl)-1,3-thiazole-5-carboxamide

371.2 B 5-(6-{[(3-fluoro(2- pyridyl))cyclobutyl]amino}pyridazin-3-yl)-2-hydroxybenzamide

380.1 B 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]thiophene-2- carboxamide

384.1 A [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl][(3-fluoro(2-pyridyl))cyclobutyl]amine

376.2 B 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3,4-thiadiazole-2- carboxamide

386.1 B {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-(1,3-thiazol-2-yl)pyridazin-3-yl)amine

342.1 B (6-(2H-1,2,3,4-tetraazol-5- yl)pyridazin-3-yl){[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

327.2 D 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3,4-oxadiazole-2- carboxamide

370.2 C 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-4-methyl-1,3- thiazole-5-carboxamide

399.2 B 2-(6-{[(4- fluorophenyl)cyclobutyl]amino}py-ridazin-3-yl)-1,3-thiazole-5- carboxamide

370.2 B 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazole-5- carboxylic acid

386.2 C 5-(6-{[(3-fluoro-2- pyridyl)cyclobutyl]amino}pyridazin-3-yl)thiophene-2-carboxamide

370.1 B 5-(6-{[(4- fluorophenyl)cyclobutyl]amino}py-ridazin-3-yl)thiophene-2- carboxamide

369.1 B 5-(6-{[(3-fluoro-2- pyridyl)cyclobutyl]amino}pyridazin-3-yl)thiophene-2-carboxylic acid

371.1 D 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazole-5- carbonitrile

367.1 B 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]thiophene-2-carboxylic acid

385.0 B 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-4-hydroxy-1,3- thiazole-5-carboxamide

401.1 B 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-3-pyrazolino[3,4- d)1,3-thiazol-3-one

398.3 D 2-[6-({1-[6-(difluoromethoxy)(2- pyridyl)]-isopropyl}amino)pyridazin-3-yl]- 1,3-thiazole-5-carboxamide

407.1 B {2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}methan-1-ol

372.2 B [6-(5-(2H-1,2,3,4-tetraazol-5-yl)(1,3-thiazol-2-yl))pyridazin-3- yl]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

410.2 B 5-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5-yl}-1.3,4- oxadiazolin-2-one

426.2 B ethyl 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-5-hydroxypyrazole- 4-carboxylate

413.1 D 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-3-pyrazolin-5-one

341.1 B 3-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl)methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5-yl}-1,2,4- triazolin-5-one

425.2 A 3-{2-[6-({[(3-fluoro-2- pyridyl)cyclobulyl]rnethyl}amino)py-ridazin-3-yl]-1,3-thiazol-5-yl}-1,2,4- oxadiazolin-5-one

426.2 B ethyl 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-4-hydroxy-1,3- thiazole-5-carboxylate

430.1 D 2-(6-{[2-(3-fluoro(2-pyridyl))-2-methylpropyl)amino}pyridazin-3- yl)-1,3-thiazole-5-carboxamide

373.2 A 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-4-methoxy-1,3- thiazole-5-carboxamide

415.1 A 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-4-methoxy-1,3- thiazole-5-carboxylic acid

416.2 C 1-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5-yl}ethan- 1-ol

386.2 B 2,2,2-trifluoro-1-{2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}ethan-1-ol

440.2 B {2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)}-N- (methylethyl)carboxamide

427.3 B ethyl 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazole-4- carboxylate

514.0 D 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-3-pyrrolino[3,4-d]1,3- thiazol-6-one

396.1 B 1-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5-yl}ethan- 1-one

384.2 C 2-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}propan-2-ol

400.3 C 1,1,1-trifluoro-2-{2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}propan-2-ol

454.2 C {2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)}-N- methylcarboxamide

399.3 A 3-(6-{[(2- pyridylcyclobutyl)methyl]amino}py-ridazin-3-yl)benzenecarbonitrile

342.1 B 3-(6-{methyl[(2- pyridylcyclobutyl)methyl]amino}py-ridazin-3-yl)benzamide

374.2 D 6-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]pyrazine-2-carbonitrile

362.1 B 6-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]pyrazine-2- carboxamide

380.2 C 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-4-hydroxy-1,3- thiazole-5-carbonitrile

383.1 D 2-(6-{[(2- pyridylcyclobutyl)methyl]amino}py-ridazin-3-yl)-1,3-thiazole-5- carboxamide

367.1 A 2-(6-{[(2- pyridylcyclobutyl)methyl]amino}py-ridazin-3-yl)-1,3-thiazole-5- carboxylic acid

368.1 C 3-{5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-thienyl}-1,2,4- triazolin-5-one

424.1 A 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,2,4-triazolin-5-one

342.2 C amino{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methane-1-thione

401.2 A 2,2,2-trifluoro-1-{2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}ethane-1,1-diol

456.2 B {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[5-(2,2,2-trifluoroethyl)(1,3-thiazol-2- yl)]pyridazin-3-yl}amine

424.2 B 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl)thiophene-2- carbonitrile

366.2 B 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]thiopheno[2,3-c]3- pyrrolin-6-one

396.2 B {6-[5-(1-amino-2,2,2- trifluoroethyl)(1,3-thiazol-2-yl)]pyridazin-3-yl}{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine

439.2 B [6-(2-aminopyrimidin-4- yl)pyridazin-3-yl]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

352.3 B 2-{5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,2,3,4-tetraazol-2- yl}acetamide

384.3 D {6-[2-(2-aminoethyl)(1,2,3,4-tetraazol-5-yl)]pyridazin-3-yl}{[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine

370.3 D [6-(3-(2H-1,2,3,4-tetraazol-5- yl)phenyl)pyridazin-3-yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine

403.1 A phenylmethyl 2-{[6-({[(3-fluoro-2-pyridyl)cyclobutyl]methyl}amino)py- ridazin-3- yl]carbonylamino}acetate

450.1 D 3-{3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]rnethyl}amino)py-ridazin-3-yl]phenyl}-1,2,4-triazolin- 5-one

418.3 B 3-{4-fluoro-3-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-1,2,4-triazolin-5-one

436.3 A {6-[5-(aminomethyl)(1,3-thiazol-2-yl)]pyridazin-3-yl}{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine

371.3 B N-((2-(6-((1-(3-fluoropyridin-2- yl)cyclobutyl)methylamino)py-ridazin-3-yl)thiazol-5-yl)methyl)-2- methylpropane-2-sulfinamide

475.3 B {6-[5-(aminoethyl)(1,3-thiazol-2-yl)]pyridazin-3-yl}{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine

385.3 B {6-[5-(3-aminooxetan-3-yl)(1,3-thiazol-2-yl)]pyridazin-3-yl}{[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine

413.2 D 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]pyrimidine-4- carboxamide

380.3 A {2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)}-N- (2-hydroxyethyl)carboxamide

429.2 A ethyl 5-chloro-2-[5-chloro-6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-1,3-thiazole-4-carboxylate

482.2 D N-{4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]pyrimidin-2- yl}acetamide

394.3 C {4-(6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]pyrimidin-2- yl}(methylsulfonyl)amine

430.3 D (2E)-3-amino-3-{2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}-2-azaprop-2-enenitrile

409.1 B N-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}methyl)acetamide

413.3 A ({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)(methylsulfonyl)amine

449.2 B N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)methoxycarboxamide

429.2 B 2,2-difluoro-1-{2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}ethan-1-ol

422.2 B N-(carbamoylmethyl)[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]carboxamide

359.1 441.3 D 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl) morpholin-4-yl ketone

455.3 C N-(2-aminoethyl){2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}carboxamide

428.4 A N-(2,3-dihydroxypropyl){2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}carboxamide

459.3 A {2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)}-N- pyrrolidin-3-ylcarboxamide

454.3 A 2-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}acetamide

399.3 B {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(5-pyrazol-4-yl(1,3-thiazol-2- yl))pyridazin-3-yl]amine

408.3 A {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(5-pyrazol-3-yl(1,3-thiazol-2- yl))pyridazin-3-yl]amine

408.3 A 4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]pyrimidine-2- carboxamide

380.3 D 6-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]pyrimidine-4- carboxamide

380.3 B [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-pyrazol-5- ylcarboxamide

368.1 B N-(carbamoylmethyl){2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}carboxamide

442.3 A 4-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}carbonyl)piperazine-2- carboxamide

497.3 B [6-(5-chloro(1,3-thiazolino[5,4-b]pyridin-2-yl))pyridazin-3-yl]{[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine

427.1 C {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-(1,3-thiazolino[5,4-b]pyridin-2- yl)pyridazin-3-yl)amine

393.1 B [6-(5-amino(1,3-thiazolino[5,4-b]pyridin-2-yl))pyridazin-3-yl]{[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine

408.1 B amino{4-fluoro-3-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}sulfonamide

447.2 A 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)3- hydroxypyrrolidinyl ketone

455.3 C 4-({2-[6-({[(3-fluoro2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}carbonyl)-1,4-thiazaperhydroine-1,1-dione

503.3 B N-(1,1-dioxothiolan-3-yl){2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}carboxamide

503.3 A {2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)}-N- [2-(methylsulfonyl)ethyl]carboxamide

491.2 A 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl) 3- hydroxypiperidyl ketone

469.3 C {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-pyrazolo[5,4-d]1,3-thiazol-5- ylpyridazin-3-yl)amine

382.1 A 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl) 4- hydroxypiperidyl ketone

469.3 C 4-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}carbonyl)piperazin-2-one

468.3 C {2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)}-N- (oxolan-2-ylmethyl)carboxamide

469.3 B 1-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}carbonyl)piperidine-3- carboxamide

496.3 C [6-(3-(2H-1,2,3,4-tetraazol-5- yl)phenyl)pyridazin-3-yl][2-(3-fluoro(2-pyridyl))-2- methylpropyl]amine

391.3 B 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazolino[5,4- b]pyridine-5-carboxamide

436.1 D {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(5-methoxy(1,3-thiazolino[5,4- b]pyridin-2-yl))pyridazin-3- yl]amine

423.1 D 2-[6-({[(3-f1uoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazolino[5,4- b]pyridin-5-ol

409.1 B N-((2R)-2,3-dihydroxypropyl){2-[6- ({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}carboxamide

459.3 B N-((2S)-2,3-dihydroxypropyl){2-[6- ({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}carboxamide

459.3 A N-(2-amino-3.3,3- trifluoropropyl){2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}carboxamide

496.3 B N-(3-amino-2,2-difluoropropyl){2- [6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}carboxamide

478.3 A {2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)}- NfN-dimethylcarboxamide

414.3 C N-(2.2-difluoro-3- hydroxypropyl){2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}carboxamide

479.3 A {2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)}-N- (2-oxopyrrolidin-3-yl)carboxamide

468.3 B 3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

396.3 A 4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

414.3 A 2-amino-N-({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}tnethyl)acetamide

428.1 A ((2S)pyrrolidin-2-yl)-N-({2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

A ((2R)pyrrolidin-2-yl)-N-({2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

468.2 A {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-(3-pyrrolino[3,4-d]1,3-thiazol-2- yl)pyridazin-3-yl)amine

383.1 D 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-5-(methylsulfonyl)-3- pyrrolino[3,4-d]1,3-thiazole

461.1 D N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)-2-hydroxyacetamide

429.1 A 2-[({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}methyl)amino]acetamide

428.1 B ((2S)-5-oxopyrrolidin-2-yl)-N-({2- [6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

482.1 A N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)-2-hydroxy-2- methylpropanamide

457.1 A N-((3S)pyrrolidin-3-yl){2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}carboxamide

454.3 A N-((3R)pyrrolidin-3-yl){2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}carboxamide

454.3 A 2-[2-(6-{[1-(3-fluoro(2-pyridyl))-isopropyl]arnino}pyridazin-3-yl)- 1,3-thiazol-5-yl]acetamide

373.2 D ((3S)morpholin-3-yl)-N-({2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

484.3 A N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)pyrazol-5- ylcarboxamide

465.3 A N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)imidazol-2- ylcarboxamide

465.3 A N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)pyrazol-4- ylcarboxamide

465.3 A ((4S)-2-oxoimidazolidin-4-yl)-N- ({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

483.3 A ((3S)-6-oxo(3-piperidyl))-N-({2-[6- ({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

496.3 A 2H-1,2,3-triazol-4-yl-N-({2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

466.3 A (2S)-2-amino-N-({2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)-3-hydroxypropanamide

458.3 A (2R)-2-amino-N-({2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)-3-hydroxypropanamide

458.3 A ((2S)-4-acetylpiperazin-2-yl)-N- ({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

525.3 A [(2S)-4-(methylsulfonyl)piperazin-2-yl]-N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)carboxamide

562.3 A ((3S)morpholin-3-yl)-N-({2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

484.2 A 1H-1,2,4-triazol-5-yl-N-({2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

466.2 A ((2R)-6-oxo(2-piperidyl))-N-({2-[6- ({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

495.2 A N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)imidazol-5- ylcarboxamide

465.2 A 2-amino-N-({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)-2-methylpropanamide

456.2 A (2S)-2-amino-N-({2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)propanamide

442.2 A N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)(2-hydroxyimidazol-5-yl)carboxamide

481.2 A (2S)-2-amino-N-({2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)-3-hydroxy-3- methylbutanamide

486.3 A (2R)-2-amino-N-({2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)propanamide

442.2 A ((3R)-1,1-dioxo(1,4- thiazaperhydroin-3-yl))-N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)carboxamide

532.1 A ((2S)-4,4-difluoropyrrolidin-2-yl)-N- ({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

504.2 A tert-butyl (2S)-4,4-difluoro-2-[N- ({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carbamoyl]pyrrolidine- carboxylate

604.2 B ((2S)-4,4-difluoro-1- formylpyrrolidin-2-yl)-N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)carboxamide

532.1 A ((2R,4R)-4-fluoropyrrolidin-2-yl)-N- ({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

486.1 A N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)-2-methylpropanamide

441.3 A 4-fluoro-3-(6-{[1-(3-fluoro(2- pyridyl))-isopropyl]amino}pyridazin-3- yl)benzamide

370.2 B amino-N-({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)amide

414.1 A ((3S)-1,1-dioxo(1,4- thiazaperhydroin-3-yl))-N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)carboxamide

532.3 A N-({2-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-1,3-thiazol-5-yl}methyl)acetamide

431.3 B N-({2-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-1,3-thiazol-5-yl}methyl)acetamide

431.2 B ((2S)pyrrolidin-2-yl)-N-{[2-(6-{[2- (3-fluoro(2-pyridyl))-2-methylpropyl]amino}pyridazin-3- yl)(1,3-thiazol-5-yl)]methyl}carboxamide

456.3 B 2-(6-{[1-(3-chloro(2-pyridyl))- isopropyl]amino}pyridazin-3-yl)-1,3-thiazole-5-carboxamide

375.2 B 4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

414.3 B 4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyc!obutyl]methyl}amino)py- ridazin-3-yl]benzenecarbonitrile

396.3 B 3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-4-hydroxybenzamide

412.3 B 4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzoic acid

415.3 A 3-(6-{[2-(3-chloro(2-pyridyl))-2-methylpropyl]amino}pyridazin-3- yl)benzamide

382.2 A 3-(6-{[2-(3-chloro(2-pyridyl))-2-methylpropyl]amino}pyridazin-3- yl)-4-fluorobenzamide

400.3 A N-((2R)-2,3-dihydroxypropyl){4- fluoro-3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]phenyl}carboxamide

488.3 A N-((3R)pyrrolidin-3-yl){4-fluoro-3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]phenyl}carboxamide

483.3 B N-((3S)pyrrolidin-3-yl){4-fluoro-3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]phenyl}carboxamide

483.3 B [6-(3-(2H-1,2,3,4-tetraazol-5-yl)phenyl)pyridazin-3-yl]{[3-fluoro- 1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

421.1 A 3-(6-{[2-(3-chloro(2-pyridyl))-2-methylpropyl]amino}pyridazin-3- yl)benzenecarbonitrile

364.2 B 3-(6-{[2-(3-chloro(2-pyridyl))-2-methylpropyl]amino}pyridazin-3- yl)-4-fluorobenzenecarbonitrile

382.2 B 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazole-5- sulfonamide

421.2 B (aminocyclopropyl)-N-({2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

454.2 A (N-{1-[N-({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carbamoyl]- isopropyl}carbamoyloxy)ethyl 2- methylpropanoate

614.1 A 3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzoic acid

397.2 A 3-(6-{[(3-fluoro-1-(2- pyridyl)cyclobutyl)methyl]amino}py-ridazin-3-yl)benzoic acid

379.3 A 3-(6-{[(3-fluoro-1-(2- pyridyl)cyclobutyl)methyl]amino}py-ridazin-3-yl)benzoic acid

379.3 B 3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzenecarbonitrile

378.2 B N-((2S)-2,3-dihydroxypropyl){4- fluoro-3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]phenyl}carboxamide

488.3 A methyl 4-fluoro-3-[6-({[3-fluoro-1- (3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzoate

429.3 B {4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-methylcarboxamide

428.3 A {4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-(methylethyl)carboxamide

456.3 A methyl 3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzoate

411.3 B methylethyl 4-fluoro-3-[6-({[3- fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzoate

457.3 B 6-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]imidazo[2,1-b]1,3- thiazoline-3-carboxamide

424.1 A 6-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]imidazo[2,1-b]1,3- thiazoline-3-carboxylic acid

425.1 A 6-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]imidazo[2(1-b]1,3-thiazoline-3-carboxamide

442.1 A N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl){3- [benzylamino]oxetan-3-yl}carboxamide

560.2 A 3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl)benzenesulfonamide

432.2 B {5-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1H-indazol-3-yl)}(methylsulfonyl)amine

486.3 A {[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[3-(methylamino)(1H-indazol-5- yl)]pyridazin-3-yl}amine

422.3 A {6-[3-(ethylamino)(1H-indazol-5-yl)]pyridazin-3-yl}{[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine

434.3 A [6-(3-amino(1H-indazol-5- yl))pyridazin-3-yl]{[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine

408.3 A ethyl 2-fluoro-5-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzoate

443.3 C 2-fluoro-5-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzoic acid

415.3 B 2-{4-fluoro-3-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}acetamide

410.1 B methyl 2-{4-fluoro-3-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl)phenyl}acetate

425.1 B N-({4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}methyl)acetamide

442.4 B N-({3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}methyl)acetamide

424.3 B {2-fluoro-5-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-methylcarboxamide

428.3 C N-ethyl{2-fluoro-5-[6-({[3-fluoro-1- (3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}carboxamide

442.3 C methyl 5-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-(methylamino)benzoate

440.3 B ethyl 5-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-(methylamino)benzoate

454.3 A {3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}methan-1-ol

383.2 B 2-[2-(6-{[2-(3-chloro(2-pyridyl))-2-methylpropyl]amino}pyridazin-3- yl)-1,3-thiazol-5-yl]acetamide

403.2 B 2-amino-N-{[2-(6-{[2-(3-chloro(2- pyridyl))-2-methylpropyl]amino}pyridazin-3- yl)(1,3-thiazol-5-yl)]methyl}-2-methylpropanamide

460.1 A ((2S)azetidin-2-yl)-N-({2-[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

454.1 A ethyl 2-{2-[6-({[(3-fluoro-2-pyridyl)cyclobutyl]methyl}amino)py- ridazin-3-yl]-1(3-thiazol-4-yl}acetate

428.1 C 2-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl)methyl}amino)py-ridazin-3-yl]-1,3-thiazol-4- yl}acetamide

399.2 D 6-(6-{[1-(3-chloro(2-pyridyl))- isopropyl]amino}pyridazin-3-yl)imidazo[2,1-b]1,3-thiazoline-3- carboxamide

414.1 B 6-(6-{[2-(3-chloro(2-pyridyl))-2-methylpropyl]amino}pyridazin-3- yl)imidazo[2,1-b]1,3-thiazoline-3-carboxamide

428.1 A 6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazine-3-carboxamide

302.2 D 2-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)}-2- methylpropanenitrile

409.1 D 2-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)}-2- methylpropanamide

427.1 D 3-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}propanamide

413.1 B 3-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-lhiazol-5- yl}propanoic acid

414.1 B methyl 3-{2-[6-({[(3-fluoro-2-pyridyl)cyclobutyl]methyl}amino)py- ridazin-3-yl]-1,3-thiazol-5-yl}propanoate

428.1 B 6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazine-3-carboxylic acid

303.2 D [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N- methylcarboxamide

316.2 D [6-({[(3-fluoro(2- pyridyl))cyclobulyl]methyl}amino)py-ridazin-3-yl]-N,N- dimethylcarboxamide

330.3 D 2-amino-N-({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)-2-methyl-N- methylpropanamide

470.2 A 2-{2-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-1,3-thiazol-5-yl(acetamide

417.1 B 2-{2-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-1,3-thiazol-5-yl}acetic acid

418.1 B 2-[2-(6-{[1-(3-chloro(2-pyridyl))-isopropyl]amino}pyridazin-3-yl)- 1,3-thiazol-5-yl]acetamide

389.1 D (3-aminooxetan-3-yl)-N-({2-[6- ({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)carboxamide

470.1 A {3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]phenyl}-N- methylcarboxamide

392.3 B {4-fluoro-3-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-methylcarboxamide

410.3 A N-({5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-2- yl}methyl)acetamide

413.3 B N-({4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-2- yl}methyl)acetamide

413.3 D 2-{2-[6-({[1-(3-chloro(2-pyridyl))-3-fluorocyclobutyl]methyl}amino)py- ridazin-3-yl]-1,3-thiazol-5-yl}acetamide

433.2 B {3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-methylcarboxamide

410.1 A 2-{2-[6-({[(3-chloro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}acetamide

415.3 A 2-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5-yl}acetic acid

400.3 B 2-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)}-N- methylacetamide

413.3 B 2-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)}- N,N-dimethylacetamide

427.3 B [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-isoxazol-3- ylcarboxamide

369.2 B [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-(1,3-oxazol-2- yl)carboxamide

369.2 D [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-(1,3-thiazol-2- yl)carboxamide

385.2 A [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-(1,3,4-thiadiazol- 2-yl)carboxamide

386.2 B [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-imidazol-2- ylcarboxamide

368.3 C N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)-2-methyl-2-(methylamino)propanamide

470.3 A [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-(1-methylpyrazol- 3-yl)carboxamide

382.1 C N-(1H-1,2,4-triazol-5-yl)[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]carboxamide

369.3 D N-(4-cyanoimidazol-5-yl)[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]carboxamide

393.3 C N-(4-cyanopyrazol-5-yl)[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]carboxamide

393.3 B ethyl 4-{[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]carbonylamino}-1- methylimidazole-2-carboxylate

454.3 D ethyl 2-{[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]carbonylamino}-1,3- oxazole-4-carboxylate

441.3 D N-((3S)-2-oxopyrrolidin-3-yl)[6- ({[(3-fluoro(2-pyridyl))cycIobutyl]methyl}amino)py- ridazin-3-yl]carboxamide

385.3 D N-((3R)-2-oxopyrrolidin-3-yl)[6- ({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]carboxamide

385.3 D N-ethyl{4-fluoro-3-[6-({[3-fluoro-1- (3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}carboxamide

442.3 B N-(2-fluoroethyl){4-fluoro-3-[6-({[3- fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}carboxamide

460.3 B N-(2,2-difluoroethyl){4-fluoro-3-[6- ({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}carboxamide

478.3 B {4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-(2,2,2-trifluoroethyl)carboxamide

496.3 B {4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N,N-dimethylcarboxamide

442.3 B 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-4-hydroxybenzoic acid

395.2 C 2-{[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3- yl]carbonylamino}cyclopentane- carboxamide

413.3 D [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-[(5-oxopyrrolidin- 2-yl)methyl]carboxamide

399.3 D [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-(2-oxo(3- piperidyl))carboxamide

399.3 D 4-{[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]carbonylamino}-1- methylimidazole-2-carboxamide

425.3 D 2-{[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]carbonylamino}-1,3- oxazole-4-carboxamide

412.3 D {3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-4-hydroxyphenyl}-N- methylcarboxamide

408.3 B 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-4-hydroxybenzamide

394.3 B 5-{[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3- yl]carbonylamino}pyrazole-4- carboxamide

411.3 C 5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-methoxypyridine- 3-carbonitrile

391.1 D 5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-methoxypyridine- 3-carboxamide

409.2 C 5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-oxohydropyridine- 3-carboxylic acid

396.1 D 5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-oxohydropyridine- 3-carboxamide

395.1 C [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-(pyrazol-5- ylmethyl)carboxamide

382.3 D [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-[(1-methylpyrazol- 5-yl)methyl]carboxamide

396.3 D [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-[(1-methylpyrazol- 3-yl)methyl]carboxamide

396.3 D [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-[(5-oxopyrrolidin- 3-yl)methyl]carboxamide

385.3 D N-((3S)-6-oxo(3-piperidyl))[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]carboxamide

399.3 D N-((3R)-6-oxo(3-piperidyl))[6-({[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]carboxamide

399.3 D [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-(2- pyridylmethyl)carboxamide

393.3 D [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-(3- pyridylmethyl)carboxamide

393.3 C [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-(4- pyridylmethyl)carboxamide

393.3 D [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-(1,3-thiazol-2- ylmethyl)carboxamide

399.3 D [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-N-methyl-N-(1,3- thiazol-2-ylmethyl)carboxamide

413.2 D ethyl 2-{[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]carbonylamino}-1,3- thiazole-5-carboxylate

457.3 D methyl 2-{[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]carbonylamino}-1,3- thiazole-4-carboxylate

443.2 B ethyl 2-(2-{[6-({[(3-fluoro-2-pyridyl)cyclobutyl]methyl}amino)py- ridazin-3-yl]carbonylamino}-1,3-thiazol-4-yl)acetate

471.3 A 5-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxybenzoic acid

413.1 B {3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-[2-hydroxy-1- (hydroxymethyl)ethyl]carboxamide

470.2 B {5-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxyphenyl}-N-methylcarboxamide

426.1 B 5-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxybenzamide

412.1 A {3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-4-hydroxyphenyl}-N-methylcarboxamide

426.2 B 2-{[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]carbonylamino}-1,3- thiazoIe-4-carboxamide

428.1 A {5-[6-({[(3-fluoro(2- pyridyl))cyclobulyl]methyl}amino)py-ridazin-3-yl](2-thienyl)}-N- methylcarboxamide

398.1 B 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-4,5,6- trihydrocyclopenta[1,2-d]1,3-thiazole-4-carboxamide

425.3 D 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-4,5,6- trihydrocyclopenta[1,2-d]1,3- thiazole-4-carboxylicacid

426.3 D {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-(4,5,6,7-tetrahydro-1,3- thiazolo[5,4-c]pyridin-2-yl)pyridazin-3-yl)amine

397.5 D N-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](4,5,6- trihydrocyclopenta[2,3-d]1,3-thiazol-4-yl)}methoxycarboxamide

455.1 D 2-[6-({[(3-fiuoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-4,5,6,7-tetrahydro- 1,3-thiazolo[5,4-c]pyridine-5-carboxamide

440.1 D 5-acetyl-2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-4,5,6,7-tetrahydro-1,3-thiazolo[5,4-c]pyridine

439.3 D 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-5-(methylsulfonyl)- 4,5,6,7-tetrahydro-1,3-thiazolo(5,4-c]pyridine

475.3 D {5-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxyphenyl}-N,N-dimethylcarboxamide

440.1 B 4-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobuIyl]methyl}amino)py- ridazin-3-yl]isoindolin-1-one

408.1 B 5-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]isoindolin-1-one

408.1 C 6-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobulyl]methyl}amino)py- ridazin-3-yl]isoindolin-1-one

408.1 B [6-(6-amino(4,5,6,7- tetrahydrobenzothiazol-2-yl))pyridazin-3-yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine

411.5 D amino-N-{2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](4,5,6,7-tetrahydrobenzothiazol-6- yl)}amide

454.3 D N-{3-fluoro-4-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}(methylamino)car- boxamide

443.3 A N-{4-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-methyl(methylamino)carboxamide

439.3 D N-[4-(carbamoylmethyl)(1,3- thiazol-2-yl)][6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]carboxamide

442.1 A 2-(2-{[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]carbonylamino}(1,3- thiazol-4-yl))-N-methylacetamide

456.2 A 2-{2-[6-({[1-(3-chloro(2-pyridyl))-3-fluorocyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}-N-methylacetamide

447.3 B 3-{6-[4-(3-fluoro(2-pyridyl))-2- azabicyclo[2.1.1]hex-2-yl]pyridazin-3-yl}-4- hydroxybenzamide

392.1 D ethyl 2-(5-{[6-({[(3-fluoro-2-pyridyl)cyclobutyl]methyl}amino)py- ridazin-3-yl]carbonylamino}-1,3,4-thiadiazol-2-yl)acetate

472.3 D N-[5-(carbamoylmethyl)(1,3,4-thiadiazol-2-yl)][6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]carboxamide

443.2 D N-{4-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}(methylamino)carboxamide

425.3 A 2-{2-[6-({[(3-chloro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5-yl)}-N- methylacetamide

429.2 A N-cyclopropyl{4-fluoro-3-[6-({[3- fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}carboxamide

454.3 A 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-8-hydro-3- pyrazolino[1,5-a]pyrimidin-7-one

392.1 B 7-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-4-hydro-4- imidazolino[1,2-a]pyrimidin-5-one

392.3 B {4-fluoro-5-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxyphenyl}-N-methylcarboxamide

444.1 A 4-fluoro-5-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxybenzamide

430.1 A 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-4-methyl-3- pyrazolin-5-one

355.1 D 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-4,4-dimethyl-2- pyrazolin-5-one

369.2 D {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-benzylpyridazin-3-yl]amine

349.3 D 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-4-methylpyridazin-3- yl]benzenecarbonitrile

374.1 C 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-4-methylpyridazin-3-yl]benzamide

392.1 C N-cyclobulyl{4-fluoro-3-[6-({[3- fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}carboxamide

468.3 A 4-fluoro-3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-4-methylpyridazin-3-yl]benzamide

410.1 C N-(3,3-difluorocyclobutyl){4-fluoro-3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]phenyl}carboxamide

504.3 A 4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxybenzamide

430.0 A 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-4-methylpyridazin-3-yl]-1,3- thiazole-5-carboxamide

399.1 A 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-5-methylpyridazin-3-yl]benzamide

392.1 D N-cyclopropyl{3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}carboxamide

436.3 B [6-(2-aminopyrimidin-5- yl)pyridazin-3-yl]{[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine

370.1 B N-azetidin-3-yl{3-[6-({[3-fluoro-1- (3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}carboxamide

451.2 B N-(1-acetylazetidin-3-yl){3-[6-({[3- fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}carboxamide

493.3 B {3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-[1-(methylsulfonyl)azetidin-3- yl]carboxamide

529.3 B {3-(6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-(2-hydroxy-2- methylpropyl)carboxamide

468.3 B {3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-(1-methylazetidin-3-yl)carboxamide

465.3 B {3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-oxetan-3-ylcarboxamide

452.3 B 2-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-4-methylpyridazin-3-yl]-1,3- thiazol-5-yl}acetic acid

414.1 B {2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-4-methylpyridazin-3-yl]-1,3- thiazol-5-yl}methan-1-ol

386.1 B 2-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-4-methylpyridazin-3-yl](1,3- thiazol-5-yl)}-N-methylacelamide

427.2 B 2-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-4-methylpyridazin-3-yl]-1,3- thiazol-5-yl}acetamide

413.1 B {4-fluoro-3-[6-({[3-fluoro-1-(3- ftuoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-(1-methylazetidin-3-yl)carboxamide

483.3 B N-(1-acetylazetidin-3-yl){4-fluoro-3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]phenyl}carboxamide

511.3 A {3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-(3-hydroxycyclobutyl)carboxamide

466.3 B {[(3-fluoro(2- pyridyl))cyclobulyl]methyl}{6-[5-(piperazinylmethyl)(1,3-thiazol-2- yl)]pyridazin-3-yl}amine

440.3 B {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[5-(morpholin-4-ylmethyl)(1,3-thiazol- 2-yl)]pyridazin-3-yl}amine

441.3 B 4-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}methyl)-1,4-thiazaperhydroine- 1,1-dione

489.3 D {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-{5-[(4-methylpiperazinyl)methyl](1,3- thiazol-2-yl)}pyridazin-3-yl)amine

454.3 B {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(5- {[4-(2,2,2-trifluoroethyl)piperazinyl]methyl}(1, 3-thiazol-2-yl))pyridazin-3-yl]amine

522.2 B 1-acetyl-4-({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)piperazine

482.3 D 1-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)-4- (methylsulfonyl)piperazine

518.3 D [(2S)-1-({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)piperazin-2-yl]methan- 1-ol

470.3 B [(2R)-1-({2-[6-({[(3-fluoro(2-pyridyl))cyclobulyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)piperazin-2-yl]methan- 1-ol

470.3 C N-(2H-3,4,5,6-tetrahydropyran-4-yl){3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]phenyl}carboxamide

480.3 B {3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-(3-hydroxy-3- methylcyclobutyl)carboxamide

480.3 B N-((3S)oxolan-3-yl){3-[6-({[3- fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}carboxamide

466.3 B N-((3R)oxolan-3-yl){3-[6-({[3- fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}carboxamide

466.3 B N-((3S,4S)-4-hydroxy-1,1- dioxothiolan-3-yl){3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]phenyl}carboxamide

530.3 B N-(1,1-dioxothiolan-3-yl){3-[6-({[3- fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}carboxamide

514.3 B 3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxybenzamide

412.1 A 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-hydroxybenzamide

394.2 A 5-amino-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzenecarbonitrile

393.1 A 3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-5-(trifluoromethyl)benzamide

464.1 B 5-chloro-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

430.1 B 3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-5-hydroxybenzamide

412.1 A 5-amino-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]benzamide

411.2 B {3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxyphenyl}-N-methylearboxamide

426.2 A 3-[6-({(3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxybenzenecarbonitrile

394.1 B 3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-methoxybenzenecarbonitrile

408.1 C 3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxybenzoic acid

413.1 C 5-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobulyl]methyl}amino)py- ridazin-3-yl]-2- methoxybenzamide

426.1 B N-(1,1-dioxothietan-3-yl){3-[6-({[3- fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}carboxamide

500.3 B 4-fluoro-3-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxybenzamide

412.1 A 4-fluoro-5-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxybenzamide

412.1 A {3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]phenyl}-N-[(hydroxycyclopropyl)methyl]car- boxamide

466.1 A {3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-5-methylphenyl}-N-methylcarboxamide

424.1 B 3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-5-methylbenzamide

410.0 B 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-hydroxy-5- methylbenzamide

408.2 B 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl]-2-hydroxy-5- methylbenzenecarbonitrile

390.2 B 5-bromo-3-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxybenzenecarbonitrile

454.0 A 3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2- methoxybenzamide

426.2 D {5-bromo-3-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxyphenyl}-N-methylcarboxamide

507.0 B {3-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]-2-hydroxy-5-methylphenyl}-N- methylcarboxamide

440.2 B methyl 5-[6-({[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]indole-2-carboxylate

450.2 A 5-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]indole-2-carboxamide

435.2 A 5-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]indole-2-carboxylicacid

436.2 B {5-[6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl]indol-2-yl}-N-methylcarboxamide

449.1 A [6-(6-amino(3-pyridyl))pyridazin-3- yl]{[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

369.3 A {[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[6-(methylamino)(3- pyridyl)]pyridazin-3-yl}amine

383.3 B {6-[6-(cyclopropylamino)(3-pyridyl)]pyridazin-3-yl}{[3-fluoro-1- (3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

409.3 D {6-[6-amino-5-(trifluoromethyl)(3-pyridyl)]pyridazin-3-yl}{[3-fluoro-1- (3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

437.0 B [N-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}methyl)carbamoyl]methyl acetate

470.1 A [N-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}methyl)carbamoyl]methyl(2S)-2-amino-3-methylbutanoate

528.2 A [N-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}methyl)carbamoyl]methyl (2S)-2-aminopropanoate

500.2 A {[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(6-methoxy-5-methyl(3- pyridyl))pyridazin-3-yl]amine

398.3 D [6-(6-amino-5-methyl(3- pyridyl))pyridazin-3-yl]{[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine

383.3 B (2S)-N-({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)-2-hydroxypropanamide

443.1 A (2R)-N-({2-[6-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)py- ridazin-3-yl](1,3-thiazol-5-yl)}methyl)-2-hydroxypropanamide

443.1 A 2-[({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}methyl)amino]ethan-1-ol

415.1 B N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)py-ridazin-3-yl](1,3-thiazol-5- yl)}methyl)-2-hydroxy-N- methylacetamide

443.1 B [N-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}methyl)carbamoyl]methyl (2S)- 2-((2S)-2-aminopropanoylamino)propanoate

571.1 A [N-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py-ridazin-3-yl]-1,3-thiazol-5- yl}methyl)carbamoyl]methyl (2S)-2-((2S)-2-amino-3- methylbutanoylamino)-3- methylbutanoate

627.3 A

While the present invention has been described with reference to thespecific embodiments described herein, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, modifications may be made to adapt a particularsituation, material, composition of matter and/or process to theobjective, spirit and scope of the present invention. All suchmodifications are intended to be within the scope of the claims appendedhereto.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom hydrogen, halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)OR^(a),C(O)NR^(b)R^(c), OR^(a), NR^(b)R^(c), C₆₋₁₀ aryl and 5-10 memberedheteroaryl; R² is selected from C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,5-10 membered heteroaryl and NR^(b)R^(c), wherein each of the C₃₋₈cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl and 5-10 membered heteroarylgroups is optionally substituted with 1, 2, 3, 4 or 5 substituentsselected from halogen, CN, oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,(CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 membered heterocycloalkyl,(CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 membered heteroaryl groups isoptionally substituted with 1, 2, 3, 4 or 5 R^(f) substituents; R³ isselected from hydrogen, halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C(O)OR^(a), C(O)NR^(b)R^(c), OR^(a), NR^(b)R^(c), C₆₋₁₀ aryl and 5-10membered heteroaryl; R⁴ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c) and SO₂R^(a); R⁵ andR⁶ are each independently selected from hydrogen, halogen, C₁₋₆ alkyland C₁₋₆ haloalkyl; or alternatively, R⁵ and R⁶ together with the carbonatom to which they are bound form a group selected from C₃₋₈ cycloalkyl,C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl and 3-8 memberedheterocycloalkenyl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl; R⁷is selected from C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl and 5-10membered heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents; R⁸ and R⁹, at eachoccurrence, are each independently selected from hydrogen, halogen andC₁₋₆ alkyl; X is selected from a bond, —(CH₂)_(p)—,—(CH₂)_(p)C(O)(CH₂)_(q)—, —(CH₂)_(p)O(CH₂)_(q)—, —(CH₂)_(p)S(CH₂)_(q)—,—(CH₂)_(p)NR^(d)(CH₂)_(q)—, —(CH₂)_(p)C(O)O(CH₂)_(q)—,—(CH₂)_(p)OC(O)(CH₂)_(q)—, —(CH₂)_(p)NR^(d)C(O)(CH₂)_(q)—,—(CH₂)_(p)C(O)NR^(d)(CH₂)_(q)—, —(CH₂)_(p)NR^(d)C(O)NR^(d)(CH₂)_(q)—,—(CH₂)_(p)NR^(d)SO₂(CH₂)_(q)—, and —(CH₂)_(p)SO₂NR^(d)(CH₂)_(q)—; oralternatively, X, R² and R³, together with the carbon atoms to whichthey are bound, form a 5-6 membered ring optionally containing one ormore heteroatoms selected from oxygen nitrogen and sulfur, andoptionally containing one or more double bonds, and optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents; R^(a), at eachoccurrence, is independently selected from hydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents; R^(b) and R^(c), at each occurrence, are eachindependently selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, 5-10 membered heteroaryl, C(O)R^(g), C(O)OR^(g),C(O)NR^(i)R^(j) and SO₂R^(g), wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl and 5-10 membered heteroaryl groups is optionally substitutedwith 1, 2, 3, 4 or 5 R^(f) substituents; R^(d), at each occurrence, isindependently selected from hydrogen and C₁₋₆ alkyl; R^(e), at eachoccurrence, is independently selected from hydrogen, CN, OH, C₁₋₆alkoxy, C₁₋₆ alkyl and C₁₋₆ haloalkyl; R^(f), at each occurrence, isindependently selected from halogen, CN, OR^(h), OC(O)R^(h),OC(O)OR^(h), OC(O)NR^(i)R^(j), NR^(i)R^(j), NR^(d)C(O)R^(h),NR^(d)C(O)OR^(h), NR^(d)C(O)NR^(i)R^(j), NR^(d)C(O)C(O)NR^(i)R^(j),NR^(d)C(S)R^(h), NR^(d)C(S)OR^(h), NR^(d)C(S)NR^(i)R^(j),NR^(d)C(NR^(e))NR^(i)R^(j), NR^(d)S(O)R^(h), NR^(d)SO₂R^(h),NR^(d)SO₂NR^(i)R^(j), C(O)R^(h), C(O)OR^(h), C(O)NR^(i)R^(j), C(S)R^(h),C(S)OR^(h), C(S)NR^(i)R^(j), C(NR^(e))NR^(i)R^(j), SR^(h), S(O)R^(h),SO₂R^(h), SO₂NR^(i)R^(j), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(k) substituents; or two R^(f)substituents bound to a single carbon atom, together with the carbonatom to which they are both bound, form a group selected from carbonyl,C₃₋₈ cycloalkyl and 3-8 membered heterocycloalkyl; R^(g), at eachoccurrence, is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,phenyl, naphthyl, and C₇₋₁₁ aralkyl, each optionally substituted with 1,2, 3, 4 or 5 substituents selected from halogen, CN, OH, C₁₋₆ alkoxy,C₁₋₆ alkyl and C₁₋₆ haloalkyl; R^(h), at each occurrence, isindependently selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(k) substituents; R^(i) and R^(j),and at each occurrence, are each independently selected from hydrogen,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl, 5-10 membered heteroaryl,C(O)R^(g), and C(O)OR^(g), wherein each of the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, OH, C₁₋₆ alkoxy, C₁₋₆ alkyl andC₁₋₆ haloalkyl; R^(k), at each occurrence, is independently selectedfrom halogen, CN, OH, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂,NHC(O)C₁₋₆ alkyl, NHC(O)C₇₋₁₁ aralkyl, NHC(O)OC₁₋₆ alkyl, NHC(O)OC₇₋₁₁aralkyl, OC(O)C₁₋₆ alkyl, OC(O)C₇₋₁₁ aralkyl, OC(O)OC₁₋₆ alkyl,OC(O)OC₇₋₁₁ aralkyl, C(O)C₁₋₆ alkyl, C(O)C₇₋₁₁ aralkyl, C(O)OC₁₋₆ alkyl,C(O)OC₇₋₁₁ aralkyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₇₋₁₁aralkyl substituent is optionally substituted with 1, 2 or 3substituents selected from OH, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆ alkyl, NHC(O)C₇₋₁₁ aralkyl, NHC(O)OC₁₋₆ alkyl, andNHC(O)OC₇₋₁₁ aralkyl; or two R^(k) substituents bound to a single carbonatom, together with the carbon atom to which they are both bound, form acarbonyl group; m is 0, 1 or 2; n, at each occurrence, independently is0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2; provided the compound isnot6-(4-chlorophenyl)-5-methyl-N-(2-methyl-2-(piperidin-1-yl)propyl)pyridazin-3-amine,N-(2-methyl-2-(piperidin-1-yl)propyl)-6-phenyl-5-propylpyridazin-3-amineor N-(2-methyl-2-morpholinopropyl)-6-phenyl-5-propylpyridazin-3-amine.2. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein m is
 0. 3. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein m is
 1. 4. Thecompound of claim 3, wherein R⁸ and R⁹ are each hydrogen.
 5. Thecompound of any one of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁵ and R⁶ are each C₁₋₆ alkyl.
 6. The compound of claim5, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ areeach methyl.
 7. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ and R⁶ together with the carbon atomto which they are bound form a group selected from C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl and 3-8 memberedheterocycloalkenyl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl. 8.The compound of claim 7, or a pharmaceutically acceptable salt thereof,wherein R⁵ and R⁶ together with the carbon atom to which they are boundform C₃₋₈ cycloalkyl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl. 9.The compound of claim 8, or a pharmaceutically acceptable salt thereof,wherein R⁵ and R⁶ together with the carbon atom to which they are boundform a group selected from cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl. 10.The compound of claim 9, or a pharmaceutically acceptable salt thereof,wherein R⁵ and R⁶ together with the carbon atom to which they are boundform cyclobutyl optionally substituted with 1, 2, 3, 4 or 5 substituentsselected from halogen, CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a),NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.
 11. Thecompound of claim 10, or a pharmaceutically acceptable salt thereof,wherein R⁵ and R⁶ together with the carbon atom to which they are boundform cyclobutyl optionally substituted with one or two halogens.
 12. Thecompound of claim 11, or a pharmaceutically acceptable salt thereof,wherein R⁵ and R⁶ together with the carbon atom to which they are boundform a group selected from cyclobutyl, 3-fluorocyclobutyl and3,3-difluorocyclobutyl.
 13. The compound of claim 10, wherein thecompound is of Formula V(a) or V(b), or a pharmaceutically acceptablesalt thereof:

wherein R^(m) and R^(n) are each independently selected from hydrogen,halogen and C₁₋₆ alkyl.
 14. The compound of claim 13, wherein one ofR^(m) and R^(n) is hydrogen and the other is halogen.
 15. The compoundof claim 14, wherein the halogen and R⁷ are in a trans configurationwith respect to one another on the cyclobutyl ring.
 16. The compound ofclaim 14, wherein the halogen and R⁷ are in a cis configuration withrespect to one another on the cyclobutyl ring.
 17. The compound of claim13, wherein one of R^(m) and R^(n) is hydrogen and the other isfluorine.
 18. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁷ is phenyl optionally substituted with 1, 2, 3,4 or 5 substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)OR^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.
 19. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is5-10 membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(b)C(O)R^(c),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₈ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.
 20. The compound ofclaim 19, or a pharmaceutically acceptable salt thereof, wherein R⁷ ispyridyl optionally substituted with 1, 2, 3, 4 or 5 substituentsselected from halogen, CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a),OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a), NR^(d)C(O)OR^(a),NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c), NR^(d)C(S)R^(a),NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c), NR^(d)C(NR^(e))NR^(b)R^(c),NR^(d)S(O)R^(a), NR^(d)SO₂R^(a), NR^(d)SO₂NR^(b)R^(c), C(O)R^(a),C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a), C(S)OR^(a), C(S)NR^(b)R^(c),C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆alkyl, C₁₋₈ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 memberedheterocycloalkenyl, phenyl, naphthyl, C₇₋₁₁ aralkyl, and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents.
 21. The compound of claim 20, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ is 2-pyridyl optionally substitutedwith 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo,OR^(a), OC(O)R^(a), OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c),NR^(d)C(O)R^(a), NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c),NR^(d)C(O)C(O)NR^(b)R^(c), NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a),NR^(d)C(S)NR^(b)R^(c), NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a),NR^(d)SO₂R^(a), NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a),C(O)NR^(b)R^(c), C(S)R^(a), C(S)OR^(a), C(S)NR^(b)R^(c),C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 memberedheterocycloalkenyl, phenyl, naphthyl, C₇₋₁₁ aralkyl, and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents.
 22. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein X is a bond.
 23. (canceled)
 24. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R² is phenyl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.
 25. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² is 5-10 membered heteroaryloptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalogen, CN, oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.
 26. The compound of claim 25, or apharmaceutically acceptable salt thereof, wherein R² is selected frompyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl,thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionallysubstituted with 1, 2, 3 or 4 substituents selected from halogen, CN,oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a),(CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.
 27. The compound of claim 26, or apharmaceutically acceptable salt thereof, wherein R² is selected frompyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl,thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionallysubstituted with a substituent selected from (CH₂)_(n)C(O)OR^(a) and(CH₂)_(n)C(O)NR^(b)R^(c); and optionally substituted with 1, 2 or 3additional substituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.
 28. The compound of claim 27, or apharmaceutically acceptable salt thereof, wherein R² is selected fromfuranyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl,each optionally substituted with (CH₂)_(n)C(O)NR^(b)R^(c).
 29. Thecompound of claim 26, or a pharmaceutically acceptable salt thereof,wherein R² is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl,triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl,thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyland tetrazolyl, each optionally substituted with(CH₂)_(n)NR^(d)C(O)R^(a), wherein R^(a) is C₁₋₆ alkyl or 3-8 memberedheterocycloalkyl, each optionally substituted with 1, 2 or 3 additionalsubstituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.
 30. The compound of claim 29, or apharmaceutically acceptable salt thereof, wherein R² is selected fromfuranyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl,each optionally substituted with (CH₂)_(n)NR^(d)C(O)R^(a), wherein R^(a)is selected from C₁₋₆ alkyl, C₁₋₆ alkyl-OH and C₁₋₆ alkyl-NH₂, eachoptionally substituted with 1, 2 or 3 additional substituents selectedfrom halogen, CN, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl.
 31. The compound of claim 25, or apharmaceutically acceptable salt thereof, wherein R² is selected fromindolyl, indazolyl, benzimidazolyl, benzoxazolyl and benzoisoxazolyl,each optionally substituted with 1, 2, 3 or 4 substituents selected fromhalogen, CN, oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.
 32. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is selected from hydrogen, halogen,CN, CF₃ and methyl.
 33. The compound of claim 32, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is hydrogen.
 34. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R³ isselected from hydrogen, halogen, CN, CF₃ and methyl.
 35. The compound ofclaim 34, or a pharmaceutically acceptable salt thereof, wherein R³ ishydrogen.
 36. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁴ is hydrogen.
 37. (canceled)
 38. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof.
 39. The pharmaceuticalcomposition of claim 38, wherein the pharmaceutical composition isformulated for oral, sublingual, subcutaneous, parenteral, intravenous,intranasal, topical, transdermal, intraperitoneal, intramuscular,intrapulmonary, vaginal, rectal, or intraocular administration.
 40. Thepharmaceutical composition of claim 39, wherein the pharmaceuticalcomposition is formulated for oral administration.
 41. A method for thetreatment of a disease or condition selected from neuromusculardisorders, conditions of muscle wasting, muscular myopathies,rehabilitation-related deficits, peripheral vascular disease, peripheralarterial disease, frailty, muscle atrophy and fatigue, metabolicsyndrome, chronic fatigue syndrome. and obesity comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof. 42.A method for the treatment of a disease selected from AmyotrophicLateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA) and myastheniagravis comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 43. A method for the treatmentof a disease selected from peripheral vascular disease and peripheralarterial disease comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.